Heteroaryl compounds as sodium channel blockers

ABSTRACT

The invention relates to aryl substituted compounds of Formula (I): and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein Het, G, A, R, and n are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. The inventionrelates to novel heteroaryl compounds and the use of these compounds asblockers of sodium (Na⁺) channels.

2. Background Art

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.Sodium channels are primarily responsible for generating the rapidupstroke of the action potential in neuronal cells of the centralnervous system (CNS) and peripheral nervous system (PNS). In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, that forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently 9 known members ofthe family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see Table 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, H1) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Gene Tissue TTX DiseaseType Symbol Distribution IC₅₀ (nM) Association Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegeneration Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegeneration Na_(v)1.3 SCN3A CNS 15— Pain Na_(v)1.4 SCN4A Skeletal 25 Myotonia Myotonia muscle Na_(v)1.5SCN5A Heart muscle 2,000 Arrhythmia Arrhythmia Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Erythermalgia PainNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows 90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 may play a keyrole in various pain states, including acute, inflammatory and/orneuropathic pain. Deletion of the SCN9A gene in nociceptive neurons ofmice led to an increase in mechanical and thermal pain thresholds andreduction or abolition of inflammatory pain responses (Nassar et al.,Proc Natl. Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents may beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin, J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebelleratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In addition,to the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are occasionally used to treat neuropathic pain, such as fromtrigeminal neuralgia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)).Furthermore, based on a number of similarities between chronic pain andtinnitus, (Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res.28:271-275 (1987)) it has been proposed that tinnitus should be viewedas a form of chronic pain sensation (Simpson, et al., Tip. 20:12-18(1999)). Indeed, lidocaine and carbamazepine have been shown to beefficacious in treating tinnitus (Majumdar, B. et al., Clin.Otolaryngol. 8:175-180 (1983); Donaldson, Laryngol. Otol. 95:947-951(1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

The present invention is related to the use of compounds represented byany one of Formulae I-XXI, below, and the pharmaceutically acceptablesalts, prodrugs and solvates thereof (collectively referred to herein as“Compounds of the Invention”), as blockers of sodium (Na⁺) channels.

The invention is also related to treating a disorder responsive to themodulation, in particular blockade, of sodium channels in a mammalsuffering from excess activity of said channels by administering aneffective amount of a Compound of the Invention as described herein.

Compounds useful in the present invention have not been heretoforereported. Thus, one aspect of the present invention is directed to novelcompounds of any one of Formulae I-XXI, as well as theirpharmaceutically acceptable salts, prodrugs and solvates.

Another aspect of the present invention is directed to the use of thenovel compounds of any one of Formulae I-XXI, and their pharmaceuticallyacceptable salts, prodrugs and solvates as modulators, in particular,blockers of sodium channels.

A further aspect of the present invention is to provide a method fortreating pain (e.g., acute pain, chronic pain, which includes but is notlimited to, neuropathic pain, postoperative pain and inflammatory pain,or surgical pain) by administering an effective amount of a Compound ofthe Invention to a mammal in need of such treatment. Specifically, thepresent invention provides a method for preemptive or palliativetreatment of pain by administering an effective amount of a Compound ofthe Invention to a mammal in need of such treatment.

A further aspect of the present invention is to provide a method fortreating stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,migraine, familial primary erythromelalgia, paroxysmal extreme paindisorder, cerebellar atrophy, ataxia, distonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, by administering an effectiveamount of a Compound of the Invention to a mammal in need of suchtreatment.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating a disorder responsive to the blockade ofsodium ion channels, said pharmaceutical composition containing aneffective amount of a Compound of the Invention in a mixture with one ormore pharmaceutically acceptable carriers.

Also, an aspect of the invention is to provide a method of modulating,preferably blocking, sodium channels in a mammal, wherein said methodcomprises administering to the mammal an effective amount of at leastone Compound of the Invention.

A further aspect of the invention is to provide a Compound of theInvention for use in treating pain (e.g., acute pain, chronic pain,which includes but is not limited to, neuropathic pain, postoperativepain and inflammatory pain, or surgical pain) in a mammal.

A further aspect of the invention is to provide a Compound of theInvention for use in the treatment of stroke, neuronal damage resultingfrom head trauma, epilepsy, seizures, general epilepsy with febrileseizures, severe myoclonic epilepsy in infancy, neuronal loss followingglobal and focal ischemia, migraine, familial primary erythromelalgia,paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, distonia,tremor, mental retardation, autism, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or providing local anesthesia in a mammal.

A further aspect of the present invention is to provide radiolabeledCompounds of the Invention and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the invention further provides a method forscreening a candidate compound for its ability to bind to a sodiumchannel or a sodium channel subunit using a radiolabeled Compound of theInvention. In certain embodiments, the compound is radiolabeled with ³H,¹¹C, or ¹⁴C. This competitive binding assay can be conducted using anyappropriately selected methodology. In one embodiment, the screeningmethod comprises a) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; b) titrating the mixturewith a candidate compound; and c) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

A further aspect of the invention is to provide the use of a Compound ofthe Invention in the manufacture of a medicament for treating pain in amammal. In one embodiment, the invention provides the use of a Compoundof the Invention in the manufacture of a medicament for palliative orpreemptive treatment of pain, such as acute pain, chronic pain, orsurgical pain.

A further aspect of the invention is to provide the use of a Compound ofthe Invention in the manufacture of a medicament for treating stroke,neuronal damage resulting from head trauma, epilepsy, seizures, generalepilepsy with febrile seizures, severe myoclonic epilepsy in infancy,neuronal loss following global and focal ischemia, migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, distonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia in a mammal.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is based on the use of compounds ofFormula I, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof, as blockers of Na⁺ channels. In view of this property,compounds of Formula I, and the pharmaceutically acceptable salts,prodrugs and solvates thereof, are useful for treating disordersresponsive to the blockade of sodium ion channels.

The compounds useful in this aspect of the invention are compoundsrepresented by Formula I:

and the pharmaceutically acceptable salts, prodrugs and solvatesthereof, wherein:

Het is a heteroaryl having carbon atoms and at least one nitrogen atom;

G is G¹ or G², wherein

G¹ is

and

G² is

R¹ and R² are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy,haloalkylcarbonyl, and optionally substituted arylcarbonyl;

R³ is selected from the group consisting of hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, and dialkylaminoalkyl;

each R is independently alkyl, alkenyl, alkynyl, halogen, hydroxy,cyano, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino,alkylcarbonyloxy, carboxy, aminosulfonyl, alkylsulfonylamino,alkoxycarbonyl, aminocarbonylalkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂NR^(a)R^(b),—CH(NR^(a)R^(b))CH₂OH, or —CH₂CH(NR^(a)R^(b))CH₂OH, where R^(a) andR^(b) are each independently hydrogen or C₁₋₆ alkyl;

n is 0, 1, 2, 3, 4, 5, or 6;

A is

wherein

A¹ is aryl or heteroaryl, any of which is optionally substituted;

R⁷ and R⁸ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl; and

X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR⁴—, —N(R⁵)SO₂—, or —SO₂N(R⁶)—,wherein

R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl.

Each R is attached to a carbon atom or a nitrogen atom of the heteroarylring and takes place of a hydrogen atom that would otherwise be present.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein n is 0.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein n is 1.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein n is 2.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein n is 3.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein n is 4.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein n is 5.

In one embodiment, Compounds of the Invention are compounds of FormulaI, wherein A is attached to a carbon atom of the heteroaryl ring andtakes place of a hydrogen atom that would otherwise be present.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein A is attached to a nitrogen atom of the heteroarylring and takes place of a hydrogen that would otherwise be present.

The carbon atoms in G¹ and G² to which the OH groups are attached can bechiral centers. Accordingly, the configuration at those carbon atoms canbe (R) or (S).

In compounds of Formula I, when any of R¹ or R² is hydroxyalkyl,alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, ordialkylaminoalkyl, the alkyl portion of R¹ or R² that is attached to thenitrogen atom includes at least two carbon atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having carbon atoms and 1, 2, or3 nitrogen atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having carbon atoms and 1nitrogen atom.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having carbon atoms and 2nitrogen atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having carbon atoms and 3nitrogen atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 5, 6, 9, or 10 ring atoms,wherein the ring atoms are carbon atoms and at least one nitrogen atom.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 5, 6, 9, or 10 ring atoms,wherein the ring atoms are carbon atoms and 1, 2, or 3 nitrogen atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 5, 6, 9, or 10 ring atoms,wherein the ring atoms are carbon atoms and 1 nitrogen atom.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 5, 6, 9, or 10 ring atoms,wherein the ring atoms are carbon atoms and 2 nitrogen atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 5, 6, 9, or 10 ring atoms,wherein the ring atoms are carbon atoms and 3 nitrogen atoms.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 5 ring atoms, wherein thering atoms are carbon atoms and at least one nitrogen atom. In thisembodiment, the 5-membered heteroaryl typically has 1, 2, or 3 nitrogenatoms, and preferably 1 or 2 nitrogen atoms. Typical heteroaryl groupshaving 5 ring atoms, wherein 1 ring atom is nitrogen include1H-pyrrolyl, 2H-pyrrolyl, and 3H-pyrrolyl. Typical heteroaryl groupshaving 5 ring atoms, wherein 2 ring atoms are nitrogen include pyrazolyland imidazolyl. Typical heteroaryl groups having 5 ring atoms, wherein 3ring atoms are nitrogen include 1,2,3-triazolyl and 1,2,4-triazolyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 6 ring atoms, wherein thering atoms are carbon atoms and at least nitrogen atom. In thisembodiment, the 6-membered heteroaryl typically has 1, 2, or 3 nitrogenatoms, and preferably 1 or 2 nitrogen atoms. The heteroaryl group having6 ring atoms, wherein 1 ring atom is nitrogen, is pyridinyl. Typicalheteroaryl groups having 6 ring atoms, wherein 2 ring atoms arenitrogen, include pyridazinyl, pyrimidinyl, and pyrazinyl. Typicalheteroaryl groups having 6 ring atoms, wherein 3 ring atoms arenitrogen, include 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl.Pyridinyl is preferred.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 9 ring atoms, wherein thering atoms are carbon atoms and at least one nitrogen atom. In thisembodiment, the 9-membered heteroaryl typically has 1 or 2 nitrogenatoms. Typical heteroaryl groups having 9 ring atoms, wherein one ringatom is nitrogen, include indolyl (1H-indolyl or 3H-indolyl),isoindolyl, and cyclopenta[b]pyridinyl, and preferably indolyl. Typicalheteroaryl groups having 9 ring atoms, wherein 2 ring atoms are nitrogeninclude indazolyl, benzimidazolyl, pyrrolo[2,3-c]pyridinyl, andpyrrolo[3,2-b]pyridinyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is a heteroaryl having 10 ring atoms, wherein thering atoms are carbon atoms and at least one ring nitrogen atom. In thisembodiment, the 10-membered heteroaryl typically has 1 or 2 nitrogenatoms. Typical heteroaryl groups having 10 ring atoms, wherein one ringatom is nitrogen include quinolinyl and isoquinolinyl. Typicalheteroaryl groups having 10 ring atoms, wherein 2 ring atoms arenitrogen, include cinnolinyl, quinazolinyl, naphthyridinyl,pyrido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, andpyrido[4,3-b]pyridinyl.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is selected from the group consisting ofpyridinyl, pyrimidinyl, indolyl, indazolyl, 1H-pyrrolo[3,2-b]pyridinyl,and 1H-pyrrolo[2,3-c]pyridinyl; and typically Het is pyridinyl, indolyl,or pyrimidinyl; and more typically pyridinyl or indolyl. In anotherembodiment, when Het is indolyl, G is attached to a carbon atom of theindolyl ring.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is pyridinyl and n is n1, which Compounds of theInvention have the Formula II:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G, A, and R, are as defined for Formula I and n1 is 0,1, 2, or 3. Typically, n1 is 0, 1, or 2, and preferably n1 is 0 or 1. Inanother embodiment, Compounds of the Invention are compounds of FormulaII where n1 is 0, and the pharmaceutically acceptable salts, prodrugsand solvates thereof. In another embodiment, Compounds of the Inventionare compounds of Formula H where n1 is 1, and the pharmaceuticallyacceptable salts, prodrugs and solvates thereof.

In another embodiment, Compounds of the Invention are compounds ofFormula II, wherein G and A are at 2- and 6-positions of the pyridinylring, which Compounds of the Invention have the Formula III:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G, A, R and n1 are as defined above for Formulae I orII.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is indolyl and n is n2, which Compounds of theInvention have the Formula IV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G, A, and R are as defined for Formula I and n2 is 0,1, 2, 3, 4, or 5. Typically, n2 is 0, 1, or 2, and preferably n2 is 0or 1. In another embodiment, Compounds of the Invention are compounds ofFormula IV where n2 is 0, and the pharmaceutically acceptable salts,prodrugs and solvates thereof. In another embodiment, Compounds of theInvention are compounds of Formula IV where n2 is 1, and thepharmaceutically acceptable salts, prodrugs and solvates thereof.

In another embodiment, Compounds of the Invention are compounds ofFormula IV, where G is at the 3-position of the indolyl ring, whichCompounds of the Invention have the Formula V:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A, G, R and n2 are as defined above for Formulae I orIV.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is 1H-indolyl and G is at the 3-position of theindolyl ring, and n is 0, which Compounds of the Invention have theFormula VI:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein A and G are as defined above for Formula I.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is indazolyl and G is at the 3-position of theindazolyl ring, and n is n3, which Compounds of the Invention have theFormula VII:

wherein G and A are as defined above for Formula I and n3 is 0, 1, 2, 3,or 4, and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof. In another embodiment, Compounds of the Invention are compoundsof Formula VII where n3 is 0, and the pharmaceutically acceptable salts,prodrugs and solvates thereof. In another embodiment, Compounds of theInvention are compounds of Formula VII where n3 is 1, and thepharmaceutically acceptable salts, prodrugs and solvates thereof.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is 1H-pyrrolo[3,2-b]pyridinyl and G is at the3-position of the heteroaryl ring, and n is n4, which Compounds of theInvention have the Formula VIII:

wherein A, G, and R are as defined above for Formula I and n4 is 0, 1,2, 3, or 4, and the pharmaceutically acceptable salts, prodrugs, andsolvates thereof. In another embodiment, Compounds of the Invention arecompounds of Formula VIII where n4 is 0, and the pharmaceuticallyacceptable salts, prodrugs and solvates thereof. In another embodiment,Compounds of the Invention are compounds of Formula VIII where n4 is 1,and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is 1H-pyrrolo[2,3-c]pyridinyl and G is attached atthe 3-position of the heteroaryl ring, and n is n5, which Compounds ofthe Invention have the Formula IX:

wherein A, G, and R are as defined above for Formula I and n5 is 0, 1,2, 3, or 4, and the pharmaceutically acceptable salts, prodrugs, andsolvates thereof. In another embodiment, Compounds of the Invention arecompounds of Formula IX where n5 is 0, and the pharmaceuticallyacceptable salts, prodrugs and solvates thereof. In another embodiment,Compounds of the Invention are compounds of Formula IX where n5 is 1,and the pharmaceutically acceptable salts, prodrugs and solvatesthereof.

In another embodiment, Compounds of the Invention are compounds ofFormula I, wherein Het is pyrimidinyl and n is n6, which Compounds ofthe Invention have the Formula X:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G, A, and R, are as defined for Formula I and n6 is 0,1, or 2. Typically, n6 is 0 or 1. In another embodiment, Compounds ofthe Invention are compounds of Formula X where n6 is 0, and thepharmaceutically acceptable salts, prodrugs and solvates thereof. Inanother embodiment, Compounds of the Invention are compounds of FormulaX where n6 is 1, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof.

In another embodiment, Compounds of the Invention are compounds ofFormula XI, wherein G and A are at 4- and 2-positions of the pyrimidinylring, respectively, which Compounds of the Invention have the FormulaXI:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein G, A, R and n6 are as defined above for Formulae I orX.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where G is G¹:

wherein R¹ and R² are as defined above for Formula I.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where G is G¹ and R¹ and R² are both hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where G is G¹, R¹ in G¹ is hydrogen and R² is alkyl,alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, oroptionally substituted arylcarbonyl; preferably R² is C₁₋₆ alkyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₆ alkoxy(C₂₋₆)alkyl,halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, di(C₁₋₄)alkylamino(C₂₋₆)alkyl, hydroxy,halo(C₁₋₄)alkylcarbonyl, or optionally substituted benzoyl; morepreferably R² is C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₄alkoxy(C₂₋₆)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl,di(C₁₋₂)alkylamino(C₂₋₄)alkyl, hydroxy, halo(C₁₋₄)alkylcarbonyl, orbenzoyl optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, andC₁₋₄ alkoxy.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where G is G¹, and R¹ and R² in G¹ are eachindependently selected from the group consisting of alkyl,alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl; preferably R¹ and R² are eachindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, hydroxy(C₂₋₆)alkyl, C₁₋₆ alkoxy(C₂₋₆)alkyl,halo(C₁₋₆)alkyl, halo(C₁₋₄)alkoxy(C₂₋₆)alkyl, amino(C₂₋₆)alkyl, C₁₋₄alkylamino(C₂₋₆)alkyl, di(C₁. 4)alkylamino(C₂₋₆)alkyl, hydroxy,halo(C₁₋₄)alkylcarbonyl, and optionally substituted benzoyl; andtypically R¹ and R² are each independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl, C₁₋₄alkylcarbonyl, C₁₋₄ alkoxycarbonyl, hydroxy(C₂₋₄)alkyl, C₁₋₄alkoxy(C₂₋₄)alkyl, halo(C₁₋₄)alkyl, halo(C₁₋₂)alkoxy(C₂₋₄)alkyl,amino(C₂₋₄)alkyl, C₁₋₂ alkylamino(C₂₋₄)alkyl,di(C₁₋₂)alkylamino(C₂₋₄)alkyl, hydroxy, halo(C₁. 2)alkylcarbonyl, andbenzoyl optionally substituted with 1 or 2 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, andC₁₋₄ alkoxy.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, wherein G is G¹, and where R¹ is hydrogen and R² ishydrogen, hydroxy, alkyl, or hydroxyalkyl; typically R² is hydrogen,hydroxy, C₁₋₄ alkyl, or hydroxy(C₂₋₄)alkyl; more typically R² ishydrogen, hydroxy, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl,4-hydroxybutyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl,3,4-dihydroxybutyl, or 2,4-dihydroxybutyl. In another embodiment, R¹ ishydrogen and R² is hydrogen or C₁₋₄ alkyl, such as methyl or ethyl. Inanother embodiment, R¹ is hydrogen and R² is hydroxy, 2-hydroxyethyl, or2,3-dihydroxypropyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G¹, and where G¹ is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where G is G²:

wherein R³ is as defined above for Formula I.

Typically R³ is selected from the group consisting of hydrogen, C₁₋₆alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl,halo(C₁₋₄)alkoxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₄alkylamino(C₁₋₆)alkyl, and di(C₁₋₄)alkylamino(C₁₋₆)alkyl; and preferablyR³ is selected from the group consisting of hydrogen, C₁₋₄ alkyl,hydroxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C_(m))alkyl, halo(C₁₋₄)alkyl,halo(C₁₋₂)alkoxy(C₁₋₄)alkyl, amino(C₁₋₄)alkyl, C₁₋₂alkylamino-(C₁₋₄)alkyl, and di(C₁₋₂)alkylamino(C₁₋₄)alkyl. In oneembodiment, R³ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,1,2-dihydroxyethyl, 2,3-dihydroxypropyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, ethoxymethyl, trifluoromethyl, 2-trifluoroethyl,trifluoromethoxymethyl, trifluoroethoxymethyl, aminomethyl,2-aminoethyl, methylaminomethyl, 2-(methylamino)ethyl,dimethylaminomethyl, or 2-(dimethylamino)ethyl. Typically, R³ ishydrogen or alkyl, and more preferably hydrogen or C₁₋₄ alkyl, such asmethyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI where G is G², and where G² is selected from the groupconsisting of

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-V or VII-XI, where each R is independently C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, hydroxy, cyano, hydroxy(C₁₋₆)alkyl,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, amino(C₁₋₆)alkyl, C₁₋₆alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylamino(C₁₋₆)alkyl, C₁₋₆ alkoxy,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylcarbonyloxy, carboxy, aminosulfonyl, C₁₋₆alkylsulfonylamino, C₁₋₆ alkoxycarbonyl, aminocarbonyl(C₁₋₆)alkyl, (C₁₋₆alkylaminocarbonyl)(C₁₋₆)alkyl, (di(C₁₋₆)alkylaminocarbonyl)(C₁₋₆)alkyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂NR^(a)R^(b), —CH(NR^(a)R^(b))CH₂OH, or—CH₂CH(NR^(a)R^(b))CH₂OH, where R^(a) and R^(b) are each independentlyhydrogen or C₁₋₄ alkyl. Typically, each R is independently C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, hydroxy, cyano, hydroxy(C₁₋₄)alkyl,amino, C₁₋₄ alkylamino, di(C₁₋₂)alkylamino, amino(C₁₋₄)alkyl, C₁₋₄alkylamino(C₁₋₄ alkyl, di(C₁₋₂)alkylamino(C₁₋₄)alkyl, C₁₋₄ alkoxy,aminocarbonyl, C₁₋₄ alkylaminocarbonyl, di(C₁₋₂)alkylaminocarbonyl, C₁₋₄alkylcarbonylamino, C₁₋₄ alkylcarbonyloxy, carboxy, aminosulfonyl, C₁₋₄alkylsulfonylamino, C₁₋₄ alkoxycarbonyl, aminocarbonyl(C₁₋₄)alkyl, (C₁₋₂alkylaminocarbonyl)(C₁₋₄)alkyl, (di(C₁₋₂)alkylaminocarbonyl)(C₁₋₄ alkyl,—CH(OH)C(═O)NH₂, —CH(OH)CH₂NR^(a)R^(b), —CH(NR^(a)R^(b))CH₂OH, or—CH₂CH(NR^(a)R^(b))CH₂OH, where R^(a) and R^(b) are each independentlyhydrogen or C₁₋₂ alkyl. More typically each R is independently halogen,cyano, hydroxy(C₁₋₄)alkyl, aminocarbonyl, carboxy, or C₁₋₄alkoxycarbonyl, such as fluoro, bromo, chloro, iodo, 2-hydroxyethyl,3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, aminocarbonyl,carboxy, methoxycarbonyl, ethoxycarbonyl, —CH(NH₂)CH₂OH, or—CH₂CH(NH₂)CH₂OH.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-V or VII-XI, where n is 0, i.e., R is absent.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —O—.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —S—.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —SO—.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —SO₂—.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —CH₂—.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —NR⁴—, wherein R⁴ is hydrogen or alkyl,preferably hydrogen or C₁₋₄ alkyl, and typically hydrogen or methyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —N(R⁵)SO₂—, where R⁵ is as defined abovefor Formula I. Preferably, R⁵ is hydrogen or C₁₋₄ alkyl, and typicallyhydrogen or methyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where X is —SO₂N(R⁶)—, where R⁶ is as defined abovefor Formula I. Preferably, R⁶ is hydrogen or C₁₋₄ alkyl, and typicallyhydrogen or methyl.

In another embodiment, Compounds of the Invention are compounds of anyone of Formulae I-XI, where X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NH—,—N(H)SO₂—, or —SO₂N(H)—. In another embodiment, Compounds of theInvention are compounds of any one of Formulae I-XI, where X is —O—,—S—, —SO₂—, —N(H)SO₂—, or —SO₂N(H)—. In another embodiment, Compounds ofthe Invention are compounds of any one of Formulae I-XI, where X is —O—or —S—.

Typically, R⁷ and R⁸ are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen,halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano,amide, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆acylamino, thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy,carboxy, and aminocarbonyl; and more typically each of R⁷ and R⁸ isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy,and aminocarbonyl. Typically, R⁷ and R⁸ are each independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, andC₁₋₄ alkoxy. More typically, R⁷ and R⁸ are each independently selectedfrom the group consisting of hydrogen, fluoro, bromo, trifluoromethyl,and cyano.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where R⁷ and R⁸ are both hydrogen.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A¹ is an optionally substituted aryl. In oneembodiment, A¹ is unsubstituted phenyl. In another embodiment, A¹ isphenyl substituted with 1, 2, or 3 substituents each independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; preferably eachsubstituent is independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each substituent is independentlyselected from the group consisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro,amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido,C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄alkoxy, carboxy, and aminocarbonyl. Typically, the 1, 2, or 3substituents are each independently selected from the group consistingof C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy,nitro, amino, cyano, and C₁₋₄ alkoxy, and more typically are eachindependently selected from the group consisting of fluoro, bromo,trifluoromethyl, and cyano. In one embodiment, A¹ is phenyl substitutedat the 4-position. In this embodiment, the substituent is typicallyhalogen, cyano, or haloalkyl, such as trihaloalkyl, and specificallytrifluoromethyl. In another embodiment, A¹ is phenyl substituted withtwo substituents, which can be the same or different, at the 3- and4-positions. In this embodiment, the two substituents are independentlyselected from the group consisting of halogen, cyano and haloalkyl (suchas trihaloalkyl, and specifically trifluoromethyl). In anotherembodiment, A¹ is phenyl substituted with cyano and trifluoromethyl atthe 3- and 4-positions of the phenyl group, respectively.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A is A^(a) having the structure:

X is —O —, —S—, —SO—, —SO₂—, —CH₂—, —NR⁴—, —N(R⁵)SO₂— or —SO₂N(R⁶)—,where R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl; and R⁷,R⁸, R⁹, and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R⁷, R⁸, R⁹, andR¹⁰ is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R⁷, R⁸, R⁹, and R¹⁰ isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy,and aminocarbonyl. Typically, R⁷, R⁸, R⁹ and R¹⁰ are each independentlyselected from the group consisting of hydrogen, C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, andC₁₋₄ alkoxy. More typically, R⁷, R⁸, R⁹ and R¹⁰ are each independentlyselected from the group consisting of hydrogen, fluoro, bromo,trifluoromethyl, and cyano. In another embodiment, R⁷ and R⁸ are bothhydrogen and R⁹ and R¹⁰ are as defined above for A^(a). In anotherembodiment, R⁷, R⁸, and R⁹ are hydrogen and R¹⁰ is as defined above. Inthis embodiment, R¹⁰ is typically attached at the 4-position of thephenyl ring, and more typically R¹⁰ halogen, cyano, or haloalkyl, suchas trihaloalkyl, and specifically trifluoromethyl. In anotherembodiment, R⁷ and R⁸ are hydrogen and R⁹ and R¹⁰, which can be the sameor different, are at the 3- and 4-positions of the phenyl ring. In thisembodiment, R⁹ and R¹⁰ are independently selected from the groupconsisting of halogen, cyano and haloalkyl (such as trihaloalkyl, andspecifically trifluoromethyl). In another embodiment, R⁷ and R⁸ arehydrogen and R⁹ and R¹⁰ are cyano and trifluoromethyl at the 3- and4-positions of the phenyl group, respectively. In this aspect of theinvention, compounds useful in the present invention are those where Xis —O— or —S—. In another embodiment, Compounds of of the Invention arecompounds of any of Formulae I-XI, wherein A is A¹, X is —O—, —S—, —SO—,—SO₂—, —CH₂—, or —NH—, and R⁷, R⁸, R⁹ and R¹⁰ are as defined above. Inanother embodiment, X in A^(a) is —NR⁴—, and typically —NH—. In anotherembodiment, X in A^(a) is —N(R⁵)SO₂— or —SO₂N(R⁶)—, and preferably—N(R⁵)SO₂—, where R⁵ is hydrogen or C₁₋₄ alkyl, and preferably hydrogenor methyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A is A^(b) having the structure:

whereinR⁷, R⁸, R⁹, and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R⁷, R⁸, R⁹, andR¹⁰ is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R⁷, R⁸, R⁹, and R¹⁰ isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy,and aminocarbonyl. Typically, R⁷, R⁸, R⁹ and R¹⁰ are as defined abovefor A^(a).

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is indolyl, A is A^(b) attached at the 1-positionof the indolyl ring, n is 0, and G is G¹, which Compounds of theInvention have the Formula XII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R⁹, and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹, R²,R⁷, R⁸, R⁹ and R¹⁰ are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is indolyl, G is G¹, n is 0, and A is A^(b)attached to other than 1-position of the indolyl ring, which Compoundsof the Invention have the Formula XIII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R⁹ and R¹⁰ are as defined above for Formula XI. Preferabledefinitions for R¹, R², R⁷, R⁸, R⁹ and R¹⁰ are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is pyridin-2-yl, where G is attached to the2-position, A is A^(b), n is 0, and G is G¹, which Compounds of theInvention have the Formula XIV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R⁹, and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹, R²,R⁷, R⁸, R⁹ and R¹⁰ are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is pyridin-2-yl, where G is attached to the2-position, A is A^(b) attached to the 6-position of the pyridinyl ring,n is 0, and G is G¹, which Compounds of the Invention have the FormulaXV:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R⁹, and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹, R²,R⁷, R⁸, R⁹ and R¹⁰ are those described above.

In another embodiment, Compounds of the Invention include those of anyof Formulae XII-XV, where R⁷ and R⁸ are both hydrogen and R⁹ and R¹⁰ areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl (includingmonohydroxyalkyl and dihydroxyalkyl), hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl. Typically, R⁹and R¹⁰ are each independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, C₁₋₄ alkoxy, and carboxy, and moretypically R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R⁷, R⁸, R⁹, and R¹⁰ each are hydrogen. In oneembodiment, R⁷, R⁸ and R⁹ are hydrogen and R¹⁰ is alkyl, alkenyl,alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, or aminocarbonyl; preferably R¹⁰is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,or aminocarbonyl; and more preferably R¹⁰ is C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy,nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl,ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl,C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically, R¹⁰ is selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R¹⁰ is selected from the group consisting of hydrogen,fluoro, bromo, trifluoromethyl, and cyano. In one embodiment, R¹⁰ is atthe 4-position of the phenyl ring (i.e., at the para-position). In thisembodiment, the substituent is typically halogen, cyano, or haloalkyl,such as trihaloalkyl, and specifically trifluoromethyl. In anotherembodiment, R⁷ and R⁸ are both hydrogen and R⁹ and R¹⁰, which can be thesame or different, are at the 3- and 4-positions of the phenyl ring(i.e., at the meta- and para-positions). In this embodiment, R⁹ and R¹⁰are typically independently selected from the group consisting ofhalogen, cyano and haloalkyl (such as trihaloalkyl, and specificallytrifluoromethyl). In another embodiment, R⁹ is cyano and R¹⁰ istrifluoromethyl at 3- and 4-positions of the phenyl group, respectively.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A¹ is an optionally substituted heteroaryl. Inanother embodiment, A¹ is an unsubstituted heteroaryl. In anotherembodiment, A¹ is a substituted heteroaryl, and typically a heteroarylsubstituted with 1 or 2 substituents. In one embodiment, A¹ is anoptionally substituted 5-6 membered heteroaryl ring having at least onenitrogen atom. In another embodiment, A¹ is an optionally substituted6-membered heteroaryl group having at least one nitrogen atom, such aspyridyl (pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), pyrimidinyl(pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, or pyrimidin-6-yl),pyridazinyl (pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, orpyridazin-6-yl), and pyrazinyl (pyrazin-2-yl or pyrazin-3-yl).Typically, the heteroaryl group is optionally substituted with 1 or 2substituents. Typical optional substituents include alkyl, alkenyl,alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; preferablyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro,amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido,C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄alkoxy, carboxy, and aminocarbonyl. Typically, the 1 or 2 substituentsare each independently selected from the group consisting of C₁₋₄ alkyl,halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino,cyano, and C₁₋₄ alkoxy, and more typically are each independentlyselected from the group consisting of fluoro, bromo, trifluoromethyl,and cyano.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A¹ is unsubstituted or substituted pyridyl, suchas pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In one embodiment, A¹ ispyridin-2-yl, pyridin-3-yl or pyridin-4-yl optionally substituted with 1or 2 substituents each independently selected from the group consistingof alkyl (for example, C₁₋₄ alkyl, such as methyl or ethyl), haloalkyl(for example, halo(C₁₋₄)alkyl, such as trifluoromethyl) and halogen. Inanother embodiment, A¹ is pyridin-2-yl substituted at the 5-position. Inthis embodiment, the substituent is typically halogen, cyano, orhaloalkyl, such as trihaloalkyl, and specifically trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A is A^(c) having the structure:

X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR⁴—, —N(R⁵)SO₂— or —SO₂N(R⁶)—,where R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl; and R⁷,R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R⁷, R⁸, R¹¹, andR¹² is independently selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R⁷, R⁸, R¹¹, and R¹² isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R⁷, R⁸, R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R⁷, R⁸, R¹¹ and R¹² are each independently selected from thegroup consisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano.In one embodiment, R⁷ and R⁸ are both hydrogen, and R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, fluoro,bromo, trifluoromethyl, and cyano. In this aspect of the invention,compounds useful in the present invention are those where X is —O— or—S—. In another embodiment, X in A^(c) is —NR⁴—, and typically —NH—. Inanother embodiment, X in A^(c) is —N(R⁵)SO₂— or —SO₂N(R⁶)—, andpreferably —N(R⁵)SO₂—, where R⁵ is hydrogen or C₁₋₄ alkyl, andpreferably hydrogen or methyl.

In another embodiment, Compounds of the Invention include those of anyof Formulae I-XI, where A is A^(c), and R⁷ and R⁸ in A^(c) are bothhydrogen and R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl (including monohydroxyalkyl and dihydroxyalkyl), hydroxy,nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl. Typically, R¹¹ and R¹² are each independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, C₁₋₄alkoxy, and carboxy, and more typically R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, fluoro,bromo, trifluoromethyl, and cyano. In one embodiment, R⁷, R⁸, R¹¹ andR¹² each are hydrogen. In one embodiment, R⁷, R⁸ and R¹¹ are hydrogenand R¹² is alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, oraminocarbonyl; preferably R¹² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halogen, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino,cyano, amide, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆acylamino, thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy,carboxy, or aminocarbonyl; and more preferably R¹² is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically,R¹² is selected from the group consisting of hydrogen, C₁₋₄ alkyl,halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino,cyano, and C₁₋₄ alkoxy. More typically, R¹² is selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R¹² is at the 5-position of the pyridin-2-yl ring. Inthis embodiment, the substituent is typically halogen, cyano, orhaloalkyl, such as trihaloalkyl, and specifically trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A is A^(d) having the structure:

whereinR⁷, R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R⁷, R⁸, R¹¹, andR¹² is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R⁷, R⁸, R¹¹, and R¹² isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy,and aminocarbonyl. Typically, R⁷, R⁸, R¹¹ and R¹² are as defined abovefor A^(c).

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is indolyl, A is A^(d) attached at the 1-positionof the indolyl ring, n is 0, and G is G¹, which Compounds of theInvention have the Formula XVI:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹, R²,R⁷, R⁸, R¹¹ and R¹² are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is indolyl, G is G¹, n is 0, and A is A^(d)attached to other than 1-position of the indolyl ring, which Compoundsof the Invention have the Formula XVII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R¹¹ and R¹² are as defined above for Formula XVI. Preferabledefinitions for R¹, R², R⁷, R⁸, R¹¹ and R¹² are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is pyridin-2-yl, where G is attached to the2-position, A is A^(b), n is 0, and G is G¹, which Compounds of theInvention have the Formula XVIII:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹, R²,R⁷, R⁸, R¹¹ and R¹² are those described above.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is pyridin-2-yl, where G is attached to the2-position, A is A^(d) attached to the 6-position of the pyridinyl ring,n is 0, and G is G¹, which Compounds of the Invention have the FormulaXIX:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl. Preferable definitions for R¹, R²,R⁷, R⁸, R¹¹ and R¹² are those described above.

In another embodiment, A¹ is pyridin-3-yl substituted at the 6-position.In this embodiment, the substituent is typically halogen, cyano, orhaloalkyl, such as trihaloalkyl, and specifically trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A is A^(e) having the structure:

X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR⁴—, —N(R⁵)SO₂— or —SO₂N(R⁶)—,where R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl; and R⁷,R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R⁷, R⁸, R¹¹, andR¹² is independently selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R⁷, R⁸, R¹¹, and R¹² isindependently selected from the group consisting of C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, and aminocarbonyl. Typically,R⁷, R⁸, R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R⁷, R⁸, R¹¹ and R¹² are each independently selected from thegroup consisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano.In one embodiment, R⁷ and R⁸ are both hydrogen, and R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, fluoro,bromo, trifluoromethyl, and cyano. In this aspect of the invention,compounds useful in the present invention are those where X is —O— or—S—. In another embodiment, X in A^(e) is —NR⁴—, and typically —NH—. Inanother embodiment, X in A^(e) is —N(R⁵)SO₂— or —SO₂N(R⁶)—, andpreferably —N(R⁵)SO₂—, where R⁵ is hydrogen or C₁₋₄ alkyl, andpreferably hydrogen or methyl.

In another embodiment, Compounds of the Invention include those of anyof Formulae I-XI, where A is A^(c), and R⁷ and R⁸ in A^(c) are bothhydrogen and R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl (including monohydroxyalkyl and dihydroxyalkyl), hydroxy,nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl. Typically, R¹¹ and R¹² are each independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, halogen,halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, C₁₋₄alkoxy, and carboxy, and more typically R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, fluoro,bromo, trifluoromethyl, and cyano. In one embodiment, R⁷, R⁸, R¹¹ andR¹² each are hydrogen. In one embodiment, R⁷, R⁸ and R¹¹ are hydrogenand R¹² is alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, oraminocarbonyl; preferably R¹² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halogen, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino,cyano, amide, carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₆acylamino, thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy,carboxy, or aminocarbonyl; and more preferably R¹² is C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido,mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically,R¹² is selected from the group consisting of hydrogen, C₁₋₄ alkyl,halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino,cyano, and C₁₋₄ alkoxy. More typically, R¹² is selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R¹² is at the 5-position of the pyridin-2-yl ring. Inthis embodiment, the substituent is typically halogen, cyano, orhaloalkyl, such as trihaloalkyl, and specifically trifluoromethyl.

In another embodiment, Compounds of the Invention are compounds of anyof Formulae I-XI, where A is A^(f) having the structure:

whereinR⁷, R⁸, R¹¹, and R¹² are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; preferably each of R⁷, R⁸, R¹¹, andR¹² is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,and aminocarbonyl; and more preferably each of R⁷, R⁸, R¹¹, and R¹² isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl, ureido, C₁₋₄ acylamino,thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl, C₁₋₄ alkoxy, carboxy,and aminocarbonyl. Typically, R⁷, R⁸, R¹¹ and R¹² are as defined abovefor A^(e).

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is pyridin-3-yl, where G is attached to the2-position, A is A^(f), n is 0, and G is G¹, which Compounds of theInvention have the Formula XX:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof, wherein R¹ and R² are as defined above for Formula I, and R⁷,R⁸, R¹¹, and R¹² are as defined for Formula XVIII.

In another embodiment, Compounds of the Invention are compounds ofFormula I, where Het is pyridin-3-yl, where G is attached to the2-position, A is A^(f) attached to the 6-position of the pyridinyl ring,n is 0, and G is G¹, which Compounds of the Invention have the FormulaXXI:

-   and the pharmaceutically acceptable salts, prodrugs, and solvates    thereof, wherein R¹ and R² are as defined above for Formula I, and    R⁷, R⁸, R¹¹, and R¹² are as defined for Formula XIX.

In another embodiment, Compounds of the Invention include those of anyof Formulae XVI-XXI, where R⁷ and R⁸ are both hydrogen and R¹¹ and R¹²are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl (includingmonohydroxyalkyl and dihydroxyalkyl), hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl. Typically, R¹¹and R¹² are each independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,hydroxy, nitro, amino, cyano, C₁₋₄ alkoxy, and carboxy, and moretypically R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, fluoro, bromo, trifluoromethyl, and cyano. Inone embodiment, R⁷, R⁸, R¹¹, and R¹² each are hydrogen. In oneembodiment, R⁷, R⁸ and R¹¹ are hydrogen and R¹² is alkyl, alkenyl,alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano,amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy,azido, mercaptoalkyl, alkoxy, carboxy, or aminocarbonyl; preferably R¹²is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogen, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, hydroxy, nitro, amino, cyano, amide,carboxy(C₁₋₆)alkyl, C₁₋₄ alkoxy(C₁₋₆)alkyl, ureido, C₁₋₆ acylamino,thiol, C₁₋₆ acyloxy, azido, mercapto(C₁₋₆)alkyl, C₁₋₆ alkoxy, carboxy,or aminocarbonyl; and more preferably R¹² is C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halogen, halo(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl, hydroxy,nitro, amino, cyano, amide, carboxy(C₁₋₄)alkyl, C₁₋₂ alkoxy(C₁₋₄)alkyl,ureido, C₁₋₄ acylamino, thiol, C₁₋₄ acyloxy, azido, mercapto(C₁₋₄)alkyl,C₁₋₄ alkoxy, carboxy, or aminocarbonyl. Typically, R¹² is selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkyl, hydroxy, nitro, amino, cyano, and C₁₋₄ alkoxy. Moretypically, R¹² is selected from the group consisting of hydrogen,fluoro, bromo, trifluoromethyl, and cyano. In one embodiment, R¹² is atthe 5-position of the pyridinyl ring. In this embodiment, thesubstituent is typically halogen, cyano, or haloalkyl, such astrihaloalkyl, and specifically trifluoromethyl. In another embodiment,R¹² is chloro or trifluoromethyl at the 5-position of the pyridinylring.

Optional substituents attached to aryl, phenyl, and heteroaryl ringseach take the place of a hydrogen atom that would otherwise be presentin any position on the aryl, phenyl or heteroaryl rings, respectively.

In another embodiment, Compounds of the Invention include:

-   2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,-   ethyl    2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanoate,-   2,3-dihydroxy-N-methyl-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,-   2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,-   ethyl    3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxy-propanoate,-   3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide,-   3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide,-   3-(2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)-2,3-dihydroxypropanamide,    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

In another embodiment, Compounds of the Invention include:

-   (2R,3S)-2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,-   (2S,3R)-ethyl    2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanoate,-   (2S,3R)-2,3-dihydroxy-N-methyl-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propananmide,-   (2S,3R)-2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,-   (2S,3R)-ethyl    3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanoate,-   (2S,3R)-3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide,-   (2R,3S)-3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide,-   (2R,3S)-3-(2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)-2,3-dihydroxypropanamide,    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

In another embodiment, Compounds of the Invention include any of thefollowing compounds:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof.

In another embodiment, Compounds of the Invention include any of thefollowing compounds:

and the pharmaceutically acceptable salts, prodrugs, and solvatesthereof.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups are selected from straight-chain and branched-chainC₁₋₁₀ alkyl groups. Typical C₁₋₁₀ alkyl groups include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, andn-decyl, isopropyl, sec-butyl, tert-butyl, iso-butyl, iso-pentyl,neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₁₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₁₋₆ alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, iso-butyl, pentyl, 3-pentyl, hexyl, among others. In oneembodiment, useful alkyl groups are selected from straight chain C₂₋₆alkyl groups and branched chain C₃₋₆ alkyl groups. Typical C₂₋₆ alkylgroups include ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, pentyl, 3-pentyl, hexyl among others. In one embodiment,useful alkyl groups are selected from straight chain C₁₋₄ alkyl groupsand branched chain C₃₋₄ alkyl groups. Typical C₁₋₄ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl.

Useful cycloalkyl groups are selected from saturated and partiallyunsaturated (containing e.g. one or two double bonds) cyclic hydrocarbongroups containing one to three rings having 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 carbon atoms (i.e., C₃-C₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl has one or two rings. Inanother embodiment, the cycloalkyl is a C₃-C₈ cycloalkyl. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, norbornyl, decalin, adamantyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclononatrienyl,cyclodecenyl, cyclodecadienyl, cyclotetradecenyl, and cyclododecadienyland the like. In one embodiment, the cycloalkyl group contains onedouble bond. Preferably, the cycloalkyl groups containing one doublebond have 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (i.e., C₄-C₁₂cycloalkenyl). Exemplary cycloalkyl groups containing one double bondinclude cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclononenyl, cyclodecenyl, among others. In anotherembodiment, the cycloalkyl group contains two double bonds. Preferably,the cycloalkyl groups containing two double bonds have 5, 6, 7, 8, 9,10, 11, or 12 carbon atoms (i.e., C₅-C₁₂ cycloalkadienyl). Exemplarycycloalkyl groups having two double bonds include cyclopentadienyl,cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl,cyclodecadienyl, among others.

Useful alkenyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl. TypicalC₂₋₆ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl, pentenyl, and hexenyl. Typical C₂₋₄ alkenyl groups includeethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.

Useful alkynyl groups are selected from straight-chain andbranched-chain C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl. TypicalC₂₋₆ alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups. Typical C₂₋₄ alkynyl groups includeethynyl, propynyl, butynyl, and 2-butynyl groups.

Useful haloalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by one or more fluorine, chlorine, bromine or iodineatoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups).

Useful hydroxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by one or more hydroxy groups, such asmonohydroxyalkyl and dihydroxyalkyl groups (e.g., hydroxymethyl,hydroxyethyl, hydroxypropyl and hydroxybutyl groups, and especiallyhydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxybutyl,4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl).

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy,iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy,hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy).

Useful alkoxyalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with any of the above-mentioned alkoxy groups (e.g.,methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl,2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl,iso-propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy,trifluoromethoxy, and 2,2,2-trifluoroethoxy).

Useful haloalkoxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with any of the above-mentioned haloalkoxygroups (e.g., fluoromethoxymethyl, difluoromethoxymethyl,trifluoromethoxymethyl, 2-(trifluoromethoxy)ethyl, and2,2,2-trifluoroethoxymethyl).

Useful (cycloalkyl)alkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with any of the above-mentioned cycloalkylgroups (e.g., cyclopropylmethyl, 2-(cyclopropyl)ethyl,cyclopropylpropyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like).

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, more preferablyphenyl, naphthyl, and biphenyl groups.

Useful aryloxy groups include oxygen substituted by one of the arylgroups mentioned above (e.g., phenoxy).

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned aryl groups (e.g.,benzyl, phenethyl, and the like).

Useful aralkyloxy groups include oxygen substituted by one of theabove-mentioned arylalkyl groups (e.g., benzyloxy).

The term “heteroaryl” or “heteroaromatic” as employed herein refers togroups having 5 to 14 ring atoms, with 6, 10 or 14π electrons shared ina cyclic array, and containing carbon atoms and 1, 2, or 3 oxygen,nitrogen or sulfur heteroatoms, or 4 nitrogen atoms. Examples ofheteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, i-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. Typical heteroaryl groups include thienyl (e.g.,thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl(e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl).

The term “heteroaryl having carbon atoms and at least one nitrogen atom”as employed herein refers to the above mentioned “heteroaryl” compoundshaving 5 to 14 ring atoms with 6, 10 or 14 π electrons shared in acyclic array, and containing carbon atoms and 1, 2, or 3 oxygen,nitrogen or sulfur heteroatoms, or 4 nitrogen atoms, wherein at leastone of the heteroatoms is nitrogen. Examples of “heteroaryl havingcarbon atoms and at least one nitrogen atom” groups include 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. Typical heteroaryl groups include pyrrolyl (e.g.,1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yland 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl,1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl,pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g.,isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). Pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl) andindolyl are preferred.

The terms “heterocyclic” and “heterocyclo” are used herein to meansaturated or partially unsaturated 3-7 membered monocyclic, or 7-10membered bicyclic ring system, which consist of carbon atoms and fromone to four heteroatoms independently selected from the group consistingof O, N, and S, wherein the nitrogen and sulfur heteroatoms can beoptionally oxidized, the nitrogen can be optionally quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on a carbon atom or on a nitrogenatom if the resulting compound is stable. In one embodiment, the 3- to7-membered monocyclic heterocyclic ring is either a saturated, orunsaturated non-aromatic ring. A 3-membered heterocyclo can contain upto 1 heteroatom, a 4-membered heterocyclo can contain up to 2heteroatoms, a 5-membered heterocyclo can contain up to 4 heteroatoms, a6-membered heterocyclo can contain up to 4 heteroatoms, and a 7-memberedheterocyclo can contain up to 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 3- to 7-memberedheterocyclo can be attached via a nitrogen or carbon atom. A 7- to10-membered bicyclic heterocyclo contains from 1 to 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The 7- to 10-memberedbicyclic heterocyclo can be attached via a nitrogen or carbon atom.Examples of the heterocyclic rings include, but are not limited to,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxooxazolidinyl,tetrahydrothienyl, imidazolidinyl, hexahydropyrimidinyl,benzodiazepines, and the like.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups (e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-1-yl)methyl,(piperidin-1-yl)methyl, (morpholin-1-yl)methyl,(2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl,(2-oxo-imidazolidin-1-yl)methyl, (2-oxo-imidazolidin-1-yl)ethyl,(2-oxo-imidazolidin-1-yl)propyl, and the like).

As used herein, the term “amino” or “amino group” refers to —NH₂.

Useful aminoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted with an amino group.

Useful diaminoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted with two amino groups.

Useful alkylamino and dialkylamino groups are —NHR¹³ and —NR¹³R¹⁴,respectively, wherein R¹³ and R¹⁴ are each independently selected from aC₁₋₁₀ alkyl group.

Useful hydroxyalkylamino groups are —NHR¹⁵, wherein R¹⁵ is any of theabove-mentioned hydroxyalkyl groups.

Useful alkylaminoalkyl and dialkylaminoalkyl groups are any of theabove-mentioned C₁₋₁₀ alkyl groups substituted by any of theabove-mentioned alkylamino and dialkylamino groups, respectively.

As used herein, the term “aminocarbonyl” refers to —C(═O)NH₂.

As used herein, the term “aminocarbonylalkyl” refers to any of theabove-captioned C₁₋₁₀ alkyl groups substituted with an aminocarbonylgroup (e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl, and3-(aminocarbonyl)propyl).

As used herein, the term “aminosulfonyl” refers to —SO₂NH₂.

Useful alkylcarbonyl groups include a carbonyl group, i.e., —C(═O)—,substituted by any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful alkoxycarbonyl groups include a carbonyl group substituted by anyof the above-mentioned alkoxy groups (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, iso-butoxycarbonyl, sec-butoxycarbonyl, andpentyloxycarbonyl).

Useful haloalkylcarbonyl groups include a carbonyl group substituted byany of the above-mentioned haloalkyl groups (e.g., fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl,pentafluoroethylcarbonyl, 1,1-difluoroethylcarbonyl,2,2-difluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl,3,3,3-trifluoropropylcarbonyl, 4,4,4-trifluorobutylcarbonyl, andtrichloromethylcarbonyl).

Useful arylcarbonyl groups include a carbonyl group substituted by anyof the above-mentioned aryl groups (e.g., benzoyl).

Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted byone of the above-mentioned alkylcarbonyl groups.

Useful alkylcarbonylamino or acylamino groups include any of theabove-mentioned alkylcarbonyl groups attached to an amino nitrogen, suchas methylcarbonylamino.

As used herein, the term “carboxamido” or “amide” refers to a radical offormula —C(═O)NR¹⁶R¹⁷, wherein R¹⁶ and R⁷ are each independentlyhydrogen, optionally substituted C₁₋₁₀ alkyl, or optionally substitutedaryl. Exemplary carboxamido groups include —CONH₂, —CON(H)CH₃,—CON(CH₃)₂, and —CON(H)Ph and the like

Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of theabove-mentioned carboxamido groups, where R¹⁶ is H and R¹⁶ is C₁₋₁₀alkyl or where R¹⁶ and R¹⁷ are each independently selected from a C₁₋₁₀alkyl group, respectively.

Useful (alkylaminocarbonyl)alkyl and (dialkylaminocarbonyl)alkyl groupsare any of the above-mentioned C₁₋₁₀ alkyl groups substituted with analkylaminocarbonyl or a dialkylaminocarbonyl group, respectively.

As used herein, the term “sulfonamido” refers to a radical of formula—SO₂NR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ are each independently hydrogen,optionally substituted C₁₋₁₀ alkyl, or optionally substituted aryl.Exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, —SO₂N(H)Phand the like.

As used herein, the term “alkylsulfonyl” refers to —SO₂R²⁰, wherein R²⁰is any of the above-mentioned C₁₋₁₀ alkyl groups.

As used herein, the term “alkylsulfinyl” refers to —S(═O)R²⁰, whereinR²⁰ is any of the above-mentioned C₁₋₁₀ alkyl groups.

As used herein, the term “alkylsulfonylamino” refers to —N(H)SO₂R²⁰,wherein R²⁰ is any of the above-mentioned C₁₋₁₀ alkyl groups.

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by a —SH group.

As used herein, the term “carboxy” refers to —COOH.

Useful carboxyalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by —COOH.

As used herein, the term “cyano” refers to —CN.

Useful cyanoalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by —CN.

As used herein, the term “ureido” refers to —NH—C(═O)—NH₂.

As used herein, the term “azido” refers to —N₃.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the term “thiol” refers to —SH.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment. Typically, the term “about” includes therecited number±10%. Thus, “about 10” means 9 to 11.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

Optional substituents on optionally substituted groups, when nototherwise indicated, include one or more groups, typically 1, 2, or 3groups, independently selected from the group consisting of halo,halo(C₁₋₆)alkyl, aryl, heterocycle, cycloalkyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl,aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl, heterocyclo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, alkylcarbonylamino,hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C₁₋₆)alkyloxy,carboxamido, sulfonamido, azido, C₁₋₆ alkoxy, halo(C₁₋₆)alkoxy, carboxy,aminocarbonyl, and mercapto(C₁₋₄)alkyl groups mentioned above. Preferredoptional substituents include halo, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy,halo(C₁₋₄)alkoxy, and amino.

The invention disclosed herein is also meant to encompass prodrugs ofany of the disclosed compounds. As used herein, prodrugs are consideredto be any covalently bonded carriers that release the active parent drugin vivo. In general, such prodrugs will be a functional derivative of acompound of Formula I-XXI which is readily convertible in vivo, e.g., bybeing metabolized, into the required compound of Formula I-XXI.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described in, for example, Design of Prodrugs,H. Bundgaard ed., Elsevier (1985); “Drug and Enzyme Targeting, Part A,”K. Widder et al. eds., Vol. 112 in Methods in Enzymology, Academic Press(1985); Bundgaard, “Design and Application of Prodrugs,” Chapter 5 (pp.113-191) in A Textbook of Drug Design and Development, P.Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,Chem. Pharm. Bull. 32:692 (1984). Non-limiting examples of prodrugsinclude esters or amides of compounds of any of Formulae I-XXI havinghydroxyalkyl or aminoalkyl as a substituent, and these may be preparedby reacting such parent compounds with anhydrides such as succinicanhydride.

The invention disclosed herein is also intended to encompass any of thedisclosed compounds being isotopically-labelled (i.e., radiolabeled) byhaving one or more atoms replaced by an atom having a different atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled compounds of thepresent invention can be prepared by methods known in the art.

The present invention is also directed specifically to ³H, ¹¹C, or ¹⁴Cradiolabeled compounds of any of Formulae I-XXI, as well as theirpharmaceutically acceptable salts, prodrugs and solvates, and the use ofany such compounds as radioligands for their binding site on the calciumchannel. For example, one use of the labeled compounds of the presentinvention is the characterization of specific receptor binding. Anotheruse of a labeled compound of the present invention is an alternative toanimal testing for the evaluation of structure-activity relationships.For example, the receptor assay may be performed at a fixedconcentration of a labeled compound of the invention and at increasingconcentrations of a test compound in a competition assay. For example, atritiated compound of any of Formulae I-XXI can be prepared byintroducing tritium into the particular compound, for example, bycatalytic dehalogenation with tritium. This method may include reactinga suitably halogen-substituted precursor of the compound with tritiumgas in the presence of a suitable catalyst, for example, Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is meant toencompass the uses of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers maybe separated according to methods known to those of ordinary skill inthe art in view of the present disclosure. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that theyinclude both E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat”, “treating” or “treatment” is meant to encompassadministering to a subject a compound of the present invention for thepurposes of amelioration or cure, including preemptive and palliativetreatment. In one embodiment, the term “treat”, “treating” or“treatment” is meant to encompass administering to a subject a compoundof the present disclosure for the purposes of amelioration or cure.

The invention disclosed herein also encompasses the use of salts of thedisclosed compounds, including all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present invention with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The invention disclosed herein is also meant to encompass solvates ofany of the disclosed compounds. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present invention with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present invention is about 2:1, about 1:1 orabout 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of any of Formulae I-XXI may be presentas solvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that theinvention includes both solvated and unsolvated forms of compounds ofany of Formulae I-XXI. One type of solvate is a hydrate. A “hydrate”relates to a particular subgroup of solvates where the solvent moleculeis water. Solvates typically can function as pharmacologicalequivalents. Preparation of solvates is known in the art. See, forexample, M. Caira et al., J. Pharmaceut. Sci., 93(3):601-611 (2004),which describes the preparation of solvates of fluconazole with ethylacetate and with water. Similar preparation of solvates, hemisolvates,hydrates, and the like are described by E. C. van Tonder et al., AAPSPharm. Sci. Tech., 5(i):Article 12 (2004), and A. L. Bingham et al.,Chem. Commun.: 603-604 (2001). A typical, non-limiting, process ofpreparing a solvate would involve dissolving a compound of any ofFormulae I-XXI in a desired solvent (organic, water, or a mixturethereof) at temperatures above about 20° C. to about 25° C., thencooling the solution at a rate sufficient to form crystals, andisolating the crystals by known methods, e.g., filtration. Analyticaltechniques such as infrared spectroscopy can be used to confirm thepresence of the solvent in a crystal of the solvate.

Since compounds of Formulae I-XXI are modulators, in particularblockers, of sodium (Na⁺) channels, a number of diseases and conditionsmediated by sodium ion influx can be treated by employing thesecompounds. The present invention is thus directed generally to a methodfor treating a disorder responsive to the blockade of sodium channels inan animal suffering from, or at risk of suffering from, said disorder,said method comprising administering to the animal an effective amountof a compound represented by any of defined Formulae I-XXI, or apharmaceutically acceptable salt, prodrug or solvate thereof.

The present invention is further directed to a method of modulating, inparticular blocking, sodium channels in an animal in need thereof, saidmethod comprising administering to the animal at least one compoundrepresented by any of defined Formulae I-XXI, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof.

More specifically, the present invention provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, pain (e.g.,acute pain, chronic pain, which includes but is not limited toneuropathic pain, postoperative pain and inflammatory pain, or surgicalpain), migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, distonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, theinvention provides a method of treating pain. In another embodiment, thetype of pain treated is chronic pain. In another embodiment, the type ofpain treated is neuropathic pain. In another embodiment, the type ofpain treated is postoperative pain. In another embodiment, the type ofpain treated is inflammatory pain. In another embodiment, the type ofpain treated is surgical pain. In another embodiment, the type of paintreated is acute pain. In another embodiment, the treatment of pain(e.g., chronic pain, such as neuropathic pain or inflammatory pain,acute pain or surgical pain) is preemptive. In another embodiment, thetreatment of pain is palliative. In each instance, such method oftreatment requires administering to an animal in need of such treatmentan amount of a compound of the present invention that is therapeuticallyeffective in achieving said treatment. In one embodiment, the amount ofsuch compound is the amount that is effective as to block sodiumchannels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XXI, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for treating a disorder responsive to the blockade of sodiumchannels (e.g., any of the disorders listed above) in an animalsuffering from said disorder.

Furthermore, the present invention is directed to a method ofmodulating, in particular blocking, sodium channels in an animal in needthereof, said method comprising administering to the animal at least onecompound represented by any defined Formulae I-XXI, or apharmaceutically acceptable salt, prodrug or solvate thereof.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XXI, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament, in particular a medicament for modulating, in particularblocking, sodium channels, in an animal in need thereof.

Synthesis of Compounds

The compounds of the present invention can be prepared using methodsknown to those skilled in the art in view of this disclosure. Forexample, compounds of Formula I can be prepared as shown in Schemes 1and 2. Additional methods of synthesis are described and illustrated inthe working examples set forth below.

Compounds of Formula I where G is G¹ can be prepared as shown in Scheme1:

In Scheme 1, Het and A are as defined for Formula I. The Het ring can besubstituted with one or more R groups defined for Formula I.

Compounds of Formula I where G is G² can be prepared as follows:

In Scheme 2, Het, A, R¹ and R² are as defined for Formula I. The Hetring can be substituted with one or more R groups defined for Formula I.

Testing of Compounds

Representative Compounds of the Invention were assessed by sodiummobilization and/or electrophysiological assays for sodium channelblocker activity. One aspect of the present invention is based on theuse of the compounds herein described as sodium channel blockers. Basedupon this property, compounds of the present invention are considereduseful in treating a condition or disorder responsive to the blockade ofsodium ion channels, e.g., stroke, neuronal damage resulting from headtrauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, distonia, tremor, mental retardation,autism, manic depression, tinnitus, myotonia, a movement disorder, orcardiac arrhythmia, or providing local anesthesia. The compounds of thepresent invention are also expected to be effective in treating pain,such as acute pain, chronic pain, which includes but is not limited toneuropathic pain, postoperative pain and inflammatory pain, or surgicalpain.

More specifically, the present invention is directed to compounds ofFormulae I-XXI that are blockers of sodium channels. According to thepresent invention, those compounds having useful sodium channel blockingproperties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8 and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 10 μM or less,about 5 μM or less, or about 1 μM or less, in the sodium mobilizationand/or electrophysiological assays described herein. In certainembodiments, compounds of the present invention exhibit an IC₅₀ forNa_(v)1.7 of 100 μM or less, e.g., about 50 μM or less, about 10 μM orless, about 5 μM or less, or about 1 μM or less, about 0.5 μM or less,or about 0.1 μM or less. Compounds of the present invention can betested for their Na⁺ channel blocking activity using methods well knownin the art and by the following fluorescence imaging andelectrophysiological in vitro assays and/or in vive assays.

In Vitro Assay Protocols FLIPR® Assays:

Recombinant Na_(v)1.7 Cell Line: In vitro assays were performed in arecombinant cell line expressing cDNA encoding the alpha subunit(Na_(v)1.7, SCN9a, PN1, NE) of human Na_(v)1.7 (Accession No.NM_(—)002977). The cell line was provided by investigators at YaleUniversity (Cummins et al, J. Neurosci. 18(23): 9607-9619 (1998)). Fordominant selection of the Na_(v)1.7-expressing clones, the expressionplasmid co-expressed the neomycin resistance gene. The cell line wasconstructed in the human embryonic kidney cell line, HEK293, under theinfluence of the CMV major late promoter, and stable clones wereselected using limiting dilution cloning and antibiotic selection usingthe neomycin analogue, G418. Recombinant beta and gamma subunits werenot introduced into this cell line. Additional cell lines expressingrecombinant Na_(v)1.7 cloned from other species can also be used, aloneor in combination with various beta subunits, gamma subunits orchaperones.

Non-Recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels to can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO4 and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Lelurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3,333 μM, 1,111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism 4.0 Program (available fromGraphPad Software, San Diego, Calif.) to determine the IC₅₀ value forthe test article. At least one standard reference compound was evaluatedduring each experiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate was then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure was very similar, though optimaldensities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μL/well assay buffer (IXHank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)First, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 UL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) Finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μL/well. The cells wereincubated at 25° C. in the dark for 30 min. before their fluorescencewas measured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions are filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)First, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) Membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μU/well; and 3) Finally, a solution of 180 mM KCl (2×) areprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min. before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA) orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 min. before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells:

The hNa_(v)1.7 expressing HEK-293 cells were plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells were used approximately 12-48 hours after plating.

Electrophyslology:

On the day of experimentation, the 35 mm dish was placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system was used to apply test solutionsdirectly to the cell under evaluation. This system consists of an arrayof glass pipette glass connected to a motorized horizontal translator.The outlet of the shooter was positioned approximately 100 μm from thecell of interest.

Whole cell currents were recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealswere formed and the whole-cell configuration was established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 were recordedin gap-free mode. Borosilicate glass pipettes have resistance valuesbetween 1.5 and 2.0 MΩ when filled with pipette solution and seriesresistance (<5 MΩ) was compensated 75-80%. Signals were sampled at 50kHz and low pass filtered at 3 kHz.

Voltage Protocols:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols were run to establish the 1) test potential, 2)holding potential, and 3) the conditioning potential for each cell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol was run to determine the potential at which themaximal current (I_(max)) is elicited. This potential was the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels were in the inactivated state, a standard steady-stateinactivation (SSIN) protocol was run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse, V_(t), to V_(max). This protocol alsopermitted determination of the holding potential at which all channelsare in the resting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) was generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell wasdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolwas repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline was established, the test compound was appliedand block of the current elicited by the test pulse assessed. In somecases, multiple cumulative concentrations were applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound was attempted by superfusing with control solution oncesteady-state block was observed. An estimate of the K_(i) was calculatedas follows:

K=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations wereused, K_(i) was determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents was as follows. First, the standard current-voltagerelationship was tested by pulsing the cell from the holding voltage(V_(h)) of −120 mV by a series of 5 msec long square-shaped test pulsesincrementing in +10 mV steps over the membrane voltage range of −90 mVto +60 mV at the pace of stimulation of 0.5 Hz. This proceduredetermines the voltage that elicits the maximal current (V_(max)).Second, V_(h) was re-set to −120 mV and a steady-state inactivation(SSIN) curve was taken by the standard double-pulse protocol: 100 msdepolarizing pre-pulse was incremented in steps of +10 mV (voltage rangefrom −90 mV to 0 mV) immediately followed by the 5 ms long test pulse to−10 mV at the pace of stimulation of 0.2 Hz. This procedure determinesthe voltage of full inactivation (V_(full)). Third, the cell wasrepeatedly stimulated with the following protocol, first in the absenceof the test compound then in its presence. The protocol consisted ofdepolarizing the cell from the holding potential of −120 mV to theV_(full) value for 4.5 seconds then repolarizing the cell to the holdingpotential for 10 ms before applying the test pulse to the V_(max) for 5ms. The amount of inhibition produced by the test compound wasdetermined by comparing the current amplitude elicited by the test pulsein the absence and presence of the compound.

In a further alternative, the voltage clamp protocol to examinehNa_(v)1.7 currents was as follows. After establishing the whole-cellconfiguration in voltage clamp mode, two voltage protocols were run toestablish: 1) the holding potential; and 2) the test potential for eachcell.

Resting Block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol was run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (Vh1) was 20 mV morehyperpolarized than the first potential where inactivation was observedwith the inactivation protocol.

From this holding potential a standard I-V protocol was run to determinethe potential at which the maximal current (Imax) is elicited. Thispotential was the test potential (Vt).

The compound testing protocol was a series of 10 ms depolarizations fromthe Vht (determined from the SSIN) to the Vt (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline wasestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides ˜50% block) wasapplied and block of the current assessed. Washout of the compound wasattempted by superfusing with control solution once steady-state blockwas observed. The fractional response was calculated as follows:

K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of Inactivated Channels:

To assess the block of inactivated channels the holding potential wasdepolarized such that 20-50% of the current amplitude was reduced whenpulsed to the same Vt as above. The magnitude of this depolarizationdepends upon the initial current amplitude and the rate of current lossdue to slow inactivation. This was the second holding potential (Vh2).The current reduction was recorded to determine the fraction ofavailable channels at this potential (h).

h=I@Vh2/Imax.  Eq. 4

At this membrane voltage a proportion of channels was in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents were elicited by 10 ms voltage steps from Vh2 to Vtevery 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound was applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses were measuredwith respect to a projected baseline to determine K_(app).

K _(app)=[drug]*{FR/(1−FR)},  Eq. 5

where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, wereused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:

K _(i)=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Solutions and Chemicals:

For electrophysiological recordings the external solution was eitherstandard, DMEM supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contained (in mM):NaCl (10), CsF (140), CaCl₂ (1), MgCl₂ (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds were prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO didnot affect sodium currents. Vehicle solution used to establish base linewas also contacting 0.3% DMSO.

Data Analysis:

Data was analyzed off-line using Clampfit software (pClamp, v. 8; AxonInstruments) and graphed using GraphPad Prizm (v. 4.0) software.

In Vivo Assay for Pain

The compounds of the present invention can be tested for theirantinociceptive activity in the formalin model as described in Hunskaaret al., J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIHmice (20-30 g; Harlan, San Diego, Calif.) can be used in allexperiments. Food is withdrawn on the day of experiment. Mice are placedin Plexiglass jars for at least 1 hour to acclimate to the environment.Following the acclimation period mice are weighed and given either thecompound of interest administered i.p. or p.o., or the appropriatevolume of vehicle (for example, 10% Tween-80 or 0.9% saline, and otherpharmaceutically acceptable vehicles) as control. Fifteen minutes afterthe i.p. dosing, and 30 minutes after the p.o. dosing mice are injectedwith formalin (20 μL of 5% formaldehyde solution in saline) into thedorsal surface of the right hind paw. Mice are transferred to thePlexiglass jars and monitored for the amount of time spent licking orbiting the injected paw. Periods of licking and biting are recorded in5-minute intervals for 1 hour after the formalin injection. Allexperiments are done in a blinded manner during the light cycle. Theearly phase of the formalin response is measured as licking/bitingbetween 0-5 minutes, and the late phase is measured from 15-50 minutes.Differences between vehicle and drug treated groups can be analyzed byone-way analysis of variance (ANOVA). A P value <0.05 is consideredsignificant. Compounds are considered to be efficacious for treatingacute and chronic pain if they have activity in blocking both the earlyand second phase of formalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 hours before dosing. A controlgroup acts as a comparison to rats treated with a compound of FormulaeI-XXI. The control group is administered the carrier as used for thetest compound. The volume of carrier administered to the control groupis the same as the volume of carrier and test compound administered tothe test group.

Inflammatory Pain:

To assess the actions of the compounds of Formulae I-XXI on thetreatment of inflammatory pain the Freund's complete adjuvant (“FCA”)model of inflammatory pain is used. FCA-induced inflammation of the rathind paw is associated with the development of persistent inflammatorymechanical and thermal hyperalgesia and provides reliable prediction ofthe anti-hyperalgesic action of clinically useful analgesic drugs(Bartho et al., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670(1990)). The left hind paw of each animal is administered a 50 μLintraplantar injection of 50% FCA. 24 hour post injection, the animal isassessed for response to noxious mechanical stimuli by determining thepaw withdrawal threshold (PWT), or to noxious thermal stimuli bydetermining the paw withdrawal latency (PWL), as described below. Ratsare then administered a single injection of either a test compound or 30mg/Kg of a positive control compound (indomethacin). Responses tonoxious mechanical or thermal stimuli are then determined 1, 3, 5 and 24hours post administration (admin). Percentage reversal of hyperalgesiafor each animal is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{matrix}\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) \right\rbrack\end{matrix}}{\begin{matrix}\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) \right\rbrack\end{matrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anaesthesia.Following induction of anaesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover fromanaesthesia. Animals are then returned to their home cages untilbehavioral testing begins. The animals are assessed for response tonoxious mechanical stimuli by determining PWT, as described below, priorto surgery (baseline), then immediately prior to and 1, 3, and 5 hoursafter drug administration for rear paw of the animal. Percentagereversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{matrix}\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right) \right\rbrack\end{matrix}}{\begin{matrix}\left\lbrack {\left( {{baseline}\mspace{14mu} {PWT}} \right) -} \right. \\\left. \left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right) \right\rbrack\end{matrix}} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anaesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a compound of FormulaeI-XXI for the left rear paw of the animal. The animals can also beassessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injury inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

In Vivo Assay for Anticonvulsant Activity

The compounds of the present invention can be tested for in vivoanticonvulsant activity after i.v., p.o., or i.p. injection using any ofa number of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and in maleSprague-Dawley rats weighing between 200-225 g by application of current(for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration,D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 secduration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice arerestrained by gripping the loose skin on their dorsal surface andsaline-coated corneal electrodes are held lightly against the twocorneae. Rats are allowed free movement on the bench top and ear-clipelectrodes are used. Current is applied and animals are observed for aperiod of up to 30 seconds for the occurrence of a tonic hindlimbextensor response. A tonic seizure is defined as a hindlimb extension inexcess of 90 degrees from the plane of the body. Results can be treatedin a quantal manner.

Pharmaceutical Compositions

Although a compound of the present invention may be administered to amammal in the form of a raw chemical without any other componentspresent, the compound is preferably administered as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present inventioninclude all compositions where a compound of the present invention iscombined with a pharmaceutically acceptable carrier. In a preferredembodiment, the compound is present in the composition in an amount thatis effective to achieve its intended therapeutic purpose. Whileindividual needs may vary, a determination of optimal ranges ofeffective amounts of each compound is within the skill of the art.Typically, the compounds may be administered to a mammal, e.g., a human,orally at a dose of from about 0.0025 to about 1500 mg per kg bodyweight of the mammal, or an equivalent amount of a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, per day to treat, preventor ameliorate the particular disorder. A useful oral dose of a compoundof the present invention administered to a mammal is from about 0.0025to about 50 mg per kg body weight of the mammal, or an equivalent amountof the pharmaceutically acceptable salt, prodrug, or solvate thereof.For intramuscular injection, the dose is typically about one-half of theoral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily, e.g., as one or more tablets orcapsules, each containing from about 0.01 to about 50 mg of thecompound, or an equivalent amount of a pharmaceutically acceptable salt,prodrug or solvate thereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa compound of the present invention. Foremost among such animals aremammals, e.g., humans and companion animals, although the invention isnot intended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, health, and weight of the recipient,condition or disorder to be treated, kind of concurrent treatment, ifany, frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the compoundof the invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the present invention canbe administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating adisorder responsive to the blockade of sodium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a compound of the presentinvention. In one embodiment, the other therapeutic agent isadministered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A compound of the present invention (i.e., the first therapeutic agent)and the second therapeutic agent can act additively or, in oneembodiment, synergistically. Alternatively, the second therapeutic agentcan be used to treat a disorder or condition that is different from thedisorder or condition for which the first therapeutic agent is beingadministered, and which disorder or condition may or may not be acondition or disorder as defined herein. In one embodiment, a compoundof the present invention is administered concurrently with a secondtherapeutic agent; for example, a single composition comprising both aneffective amount of a compound of any of Formulae I-XXI, and aneffective amount of the second therapeutic agent can be administered.Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a combination of a compound of the presentinvention, the second therapeutic agent, and a pharmaceuticallyacceptable carrier. Alternatively, a first pharmaceutical compositioncomprising an effective amount of a compound of any of Formulae I-XXIand a second pharmaceutical composition comprising an effective amountof the second therapeutic agent can be concurrently administered. Inanother embodiment, an effective amount of a compound of the presentinvention is administered prior or subsequent to administration of aneffective amount of the second therapeutic agent. In this embodiment,the compound of the present invention is administered while the secondtherapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the compound of the presentinvention exerts its therapeutic effect for treating a disorder orcondition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbipiofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating an addictive disorder include,but are not limited to, methadone, desipramine, amantadine, fluoxetine,buprenorphine, an opiate agonist, 3-phenoxypyridine, or a serotoninantagonist.

Examples of useful therapeutic agents for treating Parkinson's diseaseand parkinsonism include, but are not limited to, carbidopa/levodopa,pergolide, bromocriptine, ropinirole, pramipexole, entacapone,tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating anxiety include, butare not limited to, benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, and triazolam; non-benzodiazepine agents, such as buspirone,gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon;tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, methohexital, pentobarbital,phenobarbital, secobarbital, and thiopental; and propanediol carbamates,such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating epilepsy or seizureinclude, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, gamma-vinyl GABA, acetazolamide,and felbamate.

Examples of useful therapeutic agents for treating stroke include, butare not limited to, anticoagulants such as heparin, agents that break upclots such as streptokinase or tissue plasminogen activator, agents thatreduce swelling such as mannitol or corticosteroids, and acetylsalicylicacid.

Examples of useful therapeutic agents for treating a pruritic conditioninclude, but are not limited to, naltrexone; nalmefene; danazol;tricyclics such as amitriptyline, imipramine, and doxepin;antidepressants such as those given below; menthol; camphor; phenol;pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating psychosis include,but are not limited to, phenothiazines such as chlorpromazinehydrochloride, mesoridazine besylate, and thoridazine hydrochloride;thioxanthenes such as chloroprothixene and thiothixene hydrochloride;clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;haloperidol; haloperidol decanoate; loxapine succinate; molindonehydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating ALS include, but arenot limited to, baclofen, neurotrophic factors, riluzole, tizanidine,benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating cognitive disordersinclude, but are not limited to, agents for treating or preventingdementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs suchas thioridazine and haloperidol; and antidepressant drugs such as thosegiven below.

Examples of useful therapeutic agents for treating a migraine include,but are not limited to, sumatriptan; methysergide; ergotamine; caffeine;and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating vomiting include, butare not limited to, 5-HT3 receptor antagonists such as ondansetron,dolasetron, granisetron, and tropisetron; dopamine receptor antagonistssuch as prochlorperazine, thiethylperazine, chlorpromazine,metoclopramide, and domperidone; glucocorticoids such as dexamethasone;and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating dyskinesia include,but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating depression include,but are not limited to, tricyclic antidepressants such as amitryptyline,amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine,maprotiline, nefazadone, nortriptyline, protriptyline, trazodone,trimipramine, and venlafaxine; selective serotonin reuptake inhibitorssuch as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine,and setraline; monoamine oxidase inhibitors such as isocarboxazid,pargyline, phenelzine, and tranylcypromine; and psychostimulants such asdextroamphetamine and methylphenidate.

A pharmaceutical composition of the present invention is preferablymanufactured in a manner which itself will be known in view of theinstant disclosure, for example, by means of conventional mixing,granulating, dragee-making, dissolving, extrusion, or lyophilizingprocesses. Thus, pharmaceutical compositions for oral use can beobtained by combining the active compound with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which may bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound may be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEO-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1

-   (2R,3S)-2,3-Dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide    (5)

(a) (E)-Ethyl3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)acrylate(3) was prepared as follows: A mixture of compound 1 (Alfe Aesar, 0.5 g,1.0 eq), compound 2, CuI (0.2 eq), K₂CO₃ (3 eq), and dimethylglycine(Aldrich, 0.1 eq) in DMF (10 mL) was heated at 160° C. for 30 minutesunder microwave. The mixture was dissolved in water/EtOAc (20 mL/100mL). The organic layer was washed with brine, concentrated and purifiedby column (silica gel, EtOAc/hexane 1/10) to afford compound 3 as awhite solid (0.4 g, 40%): ¹H-NMR (400 MHz, CDCl₃) δ: 8.42 (s, 1H),7.85-7.92 (m, 3H), 7.54 (s, 1H), 7.47-7.51 (m, 3H), 7.23-7.29 (m, 4H),7.06 (d, 1H, 8.8 Hz), 6.45 (d, 1H, 16 Hz), 4.23 (q, 2H, 7.1 Hz), 1.29(t, 3H, 7.2 Hz).

(b) 2-(4-Bromophenoxy)-5-(trifluoromethyl)pyridine (2) was prepared byheating a mixture of 4-bromophenol (1.0 eq, Aldrich),2-chloro-5-(trifluoromethyl)pyridine (0.9 eq, Aldrich), and K₂CO₃ (2 eq)in 25 mL of CH₃CN at 80° C. under argon for 14 hours. After cooling toroom temperature, water (30 mL) was added, extracted with EtOAc (2×100mL), concentrated and purified by column (silica gel, Hexanes, thenHexanes/EtOAc 10/1) to give compound 2: ¹H-NMR (400 MHz, CDCl₃) δ 8.45(s, 1H), 7.94 (ddd, 1H, 0.6, 2.6 & 8.6 Hz), 7.56 (d, 2H, 8.9 Hz),7.05-7.08 (m, 3H).

(c) (2R,3S)-Ethyl2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)-phenyl)-1H-indol-3-yl)propanoate(4) was prepared as follows: A mixture of compound 3 (0.12 g, 1.0 eq),Ad-Mix-α (1.5 eq, Aldrich), and MeSO₂NH₂ (Aldrich, 1.2 eq) in 10 mL ofi-PrOH/water (1/1) was shaken at room temperature for 4 hours. Thereaction was quenched with EtOAc/water (60 mL/20 mL). The organic layerwas separated, washed with brine, concentrated and purified by column(EtOAc/hexanes 5/4) to give compound 4 as a colorless oil (80 mg):¹H-NMR (400 MHz, CDCl₃) δ: 8.42 (s, 1H), 8.05 (s, 1H), 7.89 (1H, dd, 2.6& 8.7 Hz), 7.77-7.8 (m, 1H), 7.5-7.57 (m, 3H), 7.18-7.28 (m, 4H), 7.04(d, 1H, 8.8 Hz), 6.9 (s, 1H), 6.28 (d, 1H, 1.5 Hz), 4.36 (q, 2H, 7.1Hz), 1.37 (t, 3H, 7.2 Hz).

(d)(2R,3S)-2,3-Dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide(5) was prepared as follows: A solution of compound 4 (100 mg) and NH₃(in MeOH ˜7N, 6 mL) was shaken at room temperature for 72 hours. Thesolvent was evaporated, and the residue was purified by column(EtOAc/MeOH 8/1.5) to afford compound 5 as a white solid (70 mg): ¹H-NMR(400 MHz, CD₃OD) δ: 8.49 (s, 1H), 8.06 (1H, dd, 2.6 & 8.7 Hz), 7.82 (1H,d, 7.8 Hz), 7.56-7.65 (m, 4H), 7.38-7.41 (m, 2H), 7.15-7.25 (m, 3H),5.51 (dd, 1H, 0.8 & 2.6 Hz), 4.37 (1H, d, 2.6 Hz); LC/MS: m/z=480.2[M+Na⁺] (Calc: 457.4).

Example 2

-   (2S,3R)-Ethyl    2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanoate    (6)-   (2S,3R)-2,3-Dihydroxy-N-methyl-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide    (7)-   (2S,3R)-2,3-Dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide    (8)

(a) Compound 6 was prepared according the same procedure described inExample 1 for preparing compound 4 using Ad-mix-n (Aldrich) as astarting material. Compound 6 was obtained as a yellow solid (70%):¹H-NMR (400 MHz, CD₃OD): δ 8.37 (s, 1H), 8.04 (1H, dd, 2.6 & 8.6 Hz),7.64 (1H, d, 7.8 Hz), 7.43-7.51 (m, 4H), 7.25-7.28 (m, 2H), 7.04-7.14(m, 3H), 5.03 (dd, 1H, 0.6 & 4.6 Hz), 4.41 (d, 1H, 4.6 Hz), 4.0 (q, 2H,7.0 Hz), 1.01 (t, 3H, 7.0 Hz); LC/MS: m/z=507.1 [M+Na⁺] (Calc: 486.4).

(b) Compound 7 was prepared following the same procedure described inExample 1 for preparing compound 5 using MeNH₂ (33% in EtOH, 4 eq,Aldrich) as a starting material. Compound 7 was obtained as a whitesolid (70 mg, yield 72%): ¹H-NMR (400 MHz, CD₃OD): δ 8.49 (s, 1H), 8.16(1H, dd, 2.6 & 8.7 Hz), 7.81 (1H, d, 7.8 Hz), 7.55-7.65 (m, 4H),7.38-7.41 (m, 2H), 7.15-7.25 (m, 3H), 5.51 (dd, 1H, 1.0 & 2.6 Hz), 4.37(1H, d, 2.6 Hz), 2.84 (s, 3H); LC/MS: m/z=494.1 [M+Na^(+]) (Calc:471.4).

(c) Compound 8 was prepared following the same procedure described inExample 1 for preparing compound 5. Compound 8 was obtained as a whitesolid (100 mg): ¹H-NMR (400 MHz, CD₃OD) δ: 8.49 (s, 1H), 8.16 (1H, dd,2.6 & 8.7 Hz), 7.82 (1H, d, 7.8 Hz), 7.56-7.65 (m, 4H), 7.38-7.41 (m,2H), 7.15-7.25 (m, 3H), 5.51 (dd, 1H, 0.8 & 2.6 Hz), 4.37 (1H, d, 2.6Hz); LC/MS: m/z=480.1 [M+Na⁺] (Calc: 457.4).

Example 3

-   (2S,3R)-Ethyl    3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanoate    (14)-   (2S,3R)-3-(6-(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (15)

(a) (E)-Ethyl 3-(6-bromopyridin-2-yl)acrylate (11) was prepared asfollows: A solution of compound 9 (7 g, 37 mmol, Aldrich) in 80 mL ofTHF was added drop-wise under argon to a mixture of compound 10 (46mmol, Aldrich) and NaH (60% in mineral oil, 65 mmol, Aldrich) in 200 mLof THF at room temperature over 1 hour. The resulting solution wasstirred at room temperature for 14 hours. The reaction mixture wascooled with ice-water, slowly quenched with water (40 mL), and extractedwith EtOAc. The organic layer was washed with brine, concentrated, andpurified by column (silica gel, EtOAc/Hexanes 5/1) to get compound 11 asa white solid (7 g): ¹H-NMR (400 MHz, CDCl₃) δ 7.56-7.61 (m, 2H), 7.46(dd, 1H, 0.87 & 7.89 Hz), 7.37 (dd, 1H, 0.6 & 7.5 Hz), 6.97 (d, 1H, 15.8Hz), 4.28 (q, 2H, 7.2 Hz), 1.34 (t, 3H, 7.0 Hz).

(b) (E)-Ethyl3-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)acrylate(13) was prepared as follows: A mixture of compound 11 (0.6 g, 1.0 eq),K₂CO₃ (2 eq),5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-(trifluoromethyl)benzonitrile(12) (1.05 eq) and Pd[(o-toly)₃P]₂Cl₂ (0.2 eq) in 10 mL of DMF and water(0.1 mL) was flushed with argon and then shaken at 90° C. for 3 h. Aftercooling to room temperature, the reaction mixture was quenched withwater (20 mL), and extracted with EtOAc. The organic layer was washedwith brine, concentrated, and purified by column (EtOAc/hexanes 10/1) toafford compound 13 as a colorless oil (0.8 g): ¹H-NMR (400 MHz, CDCl₃) δ8.07 (d, 2H, 8.9 Hz), 7.74-7.84 (m, 4H), 7.39-7.43 (m, 2H), 7.3-7.33 (m,1H), 7.21 (d, 2H, 8.8 Hz), 7.12 (d, 1H, 15.8 Hz), 4.32 (q, 2H, 7.2 Hz),1.38 (t, 3H, 7.0 Hz).

(c) Compound 12 was prepared as follows:

A mixture of compound 16 (2.1 g, 10.9 mmol), compound 17 (2.4 g, 10.9mmol) and Cs₂CO₃ (3.5 g, 10.9 mmol) in DMF (14 mL) was heated at 100° C.for 4 hours. After cooling to room temperature, the mixture was filteredthrough a plug of silica gel and the plug was washed with EtOAc (50 mL).The filtrate was concentrated and the residue was purified by columnchromatography (40 g silica gel, 0-30% EtOAc/Hexane) to obtain compound12 (2.3 g, 6.9 mmol). ¹H NMR (400 MHz, CD₃OD): δ 7.81 (d, 2H, J=8.8 Hz),7.63 (d, 1H, J=8.8 Hz), 7.26 (d, 1H, J=2.4 Hz), 7.17 (dd, 1H, J1=2.4,J2=8.8 Hz), 6.98 (d, 2H, J=8.8 Hz), 1.28 (s, 12H).

(d) Compound 14 was prepared according the same procedure described inExample 1 for preparing compound 4 using Ad-mix-β (Aldrich) as astarting material. Compound 14 was obtained as a white solid (0.4 g,45%): ¹H-NMR (400 MHz, CD₃OD): δ 8.19 (d, 2H, 8.9 Hz), 7.77-7.81 (m,2H), 7.68 (d, 1H, 8.9 Hz), 7.46-7.53 (m, 2H), 7.3-7.33 (m, 1H), 7.16 (d,2H, 8.8 Hz), 5.06 (d, 1H, 3.1 Hz), 4.61 (d, 1H, 2.8 Hz), 4.08-4.17 (m,2H), 1.17 (t, 3H, 7.0 Hz); LC/MS: m/z=495.1 [M+Na⁺] (Calc: 472.4).

(e) Compound 15 was prepared following the same procedure described inExample 1 for preparing compound 5. Compound 15 was obtained as a whitesolid (150 mg): ¹H-NMR (400 MHz, CD₃OD): δ 8.21 (d, 2H, 8.9 Hz),7.87-7.91 (m, 2H), 7.79 (d, 1H, 7.5 Hz), 7.59-7.63 (m, 2H), 7.41-7.44(m, 1H), 7.26 (d, 2H, 8.8 Hz), 5.23 (d, 1H, 1.7 Hz), 4.66 (d, 1H, 1.8Hz); LC/MS: m/z=466.2 [M+Na⁺] (Calc: 443.28).

Example 4

-   (2R,3S)-3-(6-(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (19)

Compound 18 was prepared according the same procedure described inExample 1 for preparing compound 4 using Ad-mix-α (Aldrich) as startingmaterials. Compound 18 was obtained as a colorless oil (0.3 g): LC/MS:m/z=495.1 [M+Na⁺] (Calc: 472.4).

Compound 19 was prepared following the same procedure described inExample 1 for preparing compound 5. Compound 19 was obtained as a whitesolid (100 mg): ¹H-NMR (400 MHz, CD₃OD): δ 8.22 (d, 2H, 8.9 Hz),7.87-7.91 (m, 2H), 7.81 (d, 1H, 7.7 Hz), 7.59-7.63 (m, 2H), 7.42-7.44(m, 1H), 7.27 (d, 2H, 8.8 Hz), 5.23 (d, 1H, 1.7 Hz), 4.66 (d, 1H, 1.8Hz); LC/MS: m/z=466.0 [M+Na^(+]) (Calc: 443.28).

Example 5

-   (2R,3S)-3-(2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)-2,3-dihydroxypropanamide    (26)

(a) A sealed vial containing a mixture or compound 20 (Aldrich, 444 mg,3 mmol), compound 21 (Frontier Scientific, 678 mg, 3 mmol), Cs₂CO₃(Aldrich, 1.95 g, 6 mmol) and PdCl₂(PPh₃)₂ (Aldrich, 168 mg, 0.24 mmol)in mixed solvent composed of DM^(E) (3 mL), H₂O (3 mL) and ethanol (1.5mL) was heated at 100° C. under argon for two hours. After cooling toroom temperature, the mixture was extracted with EtOAc (3×25 mL). Theorganic portion was dried with Na₂SO₄, filtered and concentrated undervacuum. The residue was purified using a CombiFlash® system (silica gel12 g, 0-20% EtOAc/Hexane) to obtain compound 22 as a white solid (120mg, 19%). ¹H NMR (400 MHz, CDCl₃): δ 8.69 (1H, d, J=5.2 Hz), 7.53 (1H,d, J=16 Hz), 7.31 (1H, d, J=5.2 Hz), 7.17 (1H, d, J=16 Hz), 4.31 (2H, q,J=7.2 Hz), 1.37 (t, 3H, J=7.2 Hz).

(b) A sealed vial containing a mixture of compound 22 (70 mg, 0.33mmol), boronate 23a (103 mg, 0.33 mmol, prepared as described in Example6) and PdCl₂(PPh₃)₂ (20 mg, 0.028 mmol) in TBAF (Aldrich, 0.66 ml, 1M)was heated at 100° C. for one hour. After cooling to room temperature,the mixture was purified via Combiflash (silica gel 12 gram, 0-20%EtOAc/Hexane) to obtain compound 24 (23 mg) as a viscous liquid.

(c) To a mixture of compound 24 (23 mg, 0.06 mmol) in isopropyl alcohol(0.5 mL) and H₂O (0.5 mL) at room temperature, Admix-α (Aldrich, 82 mg)was added. The resulting mixture was stirred at room temperature for 6hours. The mixture was extracted with EtOAc (2×25 mL) and the organiclayer was dried with Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified using a CombiFlash® system (silica gel 5 g, 0-100%EtOAc/Hexane) to obtain compound 25 (12 mg). ¹H NMR (400 MHz, CDCl₃): δ8.71 (1H, d, J=5.2 Hz), 8.33 (2H, J=8.8 Hz), 7.25 (1H, d, J=5.6 Hz),7.03-6.95 (6H, m), 5.05 (1H, dd, J=2.4, 8.0 Hz), 5.63 (1H, dd, J=2.4,8.0 Hz), 4.27 (2H, q, J=7.2 Hz), 4.11 (1H, d, J=8.0 Hz), 3.27 (1H, d,J=6.4 Hz), 1.27 (3H, t, J=7.2 Hz).

(d) Compound 25 was treated with NH₃ in methanol (Aldrich, 7 N) at roomtemperature for 12 hours. After removal of the solvent, the residue wasrecrystallized from methanol to give the pure title compound 26. ¹H NMR(400 MHz, CDCl₃): δ 8.84 (1H, d, J=5.2 Hz), 8.31 (2H, d, J=8.8 Hz), 7.54(1H, d, J=5.2 Hz), 7.13-7.04 (6H, m), 6.83 (1H, bs, NH), 5.52 (1H, bs,NH), 5.43 (1H, d, J=8.4 Hz), 5.11 (1H, dd, J=4, 8.4 Hz), 4.92 (1H, d,J=8.8 Hz), 4.59 (1H, dd, J=4.4, 8.4 Hz). LC/MS: m/z=370[M+H]⁺

Example 6

-   Synthesis of    2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane    (23a)

(a) Preparation of 1-fluoro-4-(4-nitrophenoxy)benzene (27):

Method A:

500 mL round bottom flask was charged with 4-fluorophenol (11.2 g, 0.1mmol), 4-fluoro-4-nitrobenzene (14.1 g, 0.1 mol), K₂CO₃ (27.6 g, 0.2mol) and DMF (50 mL). The reaction mixture was stirred vigorously at120° C. for 4 h, cooled to room temperature, and then poured into 300 mLwater. The resulting mixture was extracted with ethyl acetate. Thecombined organic layers were dried over MgSO₄ and concentrated to givecompound 27 as an off-white solid which was used in the next stepwithout further purification (23.3 g, 100% yield). (m/z+H)=234).

Method B:

A mixture of 4-fluorophenol (30 g, 0.27 mol), 1-fluoro-4-nitrobenzene(38 g, 0.27 mol) and K₂CO₃ (37.8 g, 0.27 mol) in DMF (300 mL) was heatedat 95° C. overnight. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate (150 mL). The organic layer was washedwith water. The organic layer was dried over anhydrous MgSO₄ andconcentrated under reduced pressure to give an oily residue. The residuewas purified by automated column chromatography on silica gel using aCombiFlash® system (5% EtOAc in Hexanes) to give compound 27 as browncrystals (44 g, 70% yield, Rt=0.7, eluent (30% diethyl ether inhexanes), ¹H NMR (400 MHz, CD₃Cl): 8.2 (d, J=9.4 Hz, 2H), 7.04-7.17 (m,4H), 6.99 (d, J=9.4, 2H)).

(b) Preparation of 4-(4-fluorophenoxy)aniline (28)

Method A:

Compound 27 (23.3 g, 0.1 mol) was dissolved in ca. 50 mL MeOH and tothis solution two spatulas of palladium on carbon (5%) (ca. 50 mg) wereadded. The reaction mixture was purged with nitrogen and hydrogen (threetimes) and stirred overnight at room temperature under a balloon ofhydrogen. The palladium on carbon was removed by filtration and thefiltrate was concentrated by rotary evaporation to give compound 2 as anoff-white solid (20.4 g, 100% yield, (m/z+H)=204).

Method B:

Compound 27 (10 g, 42.9 mmol) was dissolved in 10% ethyl acetate inmethanol (250 mL) and 10% palladium on carbon (2.0 g) was added. Thereaction mixture was stirred for 5.0 h at room temperature. After thereaction was complete, the mixture was filtered through a pad of celite.The filtrate was concentrated to give compound 28 as a reddish brownsolid which was used in the next step without purification (8.5 g, 97%yield, R_(f)=0.2, eluent (25% ethyl acetate in hexanes).

(c) Preparation of 1-fluoro-4-(4-iodophenoxy)benzene (29):

Method A:

To a DME (272 mL) solution of compound 28 (20.4 g, 0.1 mol) was added asolution of H₂SO₄ (41 mL concentrated H₂SO₄ in 204 mL of H₂O) dropwise.The resulting mixture was cooled to 0° C. and a solution of NaNO₂ (10.3g, 0.15 mol) in H₂O (68 mL) was added over 20 min. After the additionwas complete, the reaction mixture was stirred at 0° C.-5° C. for anadditional 30 min and a solution of NaI (75 g, 0.5 mol) in H₂O (204 mL)was added dropwise at 0° C. After the addition was complete, the mixturewas stirred for and additional 30 min and diluted with EtOAc. Theorganic layer was collected and washed with an aqueous solution ofNa₂S₂O₃ and brine and dried over MgSO₄. The solvent was removed byevaporation and the residue solidified instantly. The pale solid product29 was used in the next step without further purification (96% yield,(m/z+H)=315).

Method B:

To a solution of p-TsOH. H₂O (56.0 g, 300 mmol) in acetonitrile (500mL), was added compound 28. The suspension was cooled to 0-5° C. andstirred for 15 min. A solution of NaNO₂ (13.8 g, 200 mmol) and KI (41.5g, 250 mmol) in H₂O (150 mL) was added slowly thereto. During theaddition, N₂ evolved. The reaction mixture was stirred for 1 h at roomtemperature. After the reaction was complete, saturated NaHCO₃ was addedto adjust the pH to 9˜10 and 2M Na₂S₂O₃ (6.0 mL) was added. The aqueouslayer was separated and extracted with ethyl acetate. The combinedorganic layers were dried with anhydrous MgSO₄ and concentrated underreduced pressure. The crude product was purified by automated columnchromatography on silica gel using a CombiFlash® system (10% ethylacetate in hexanes) to give compound 29 as a pale brown crystal (19.3 g,67% yield, R_(f)=0.8, eluent (25% ethyl acetate in hexanes), LC/MS:m/z=315 [M+H]).

(d) Preparation of2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(23a):

Method A:

A 100 mL round bottom flask was charged with compound 29 (Netchem, 5 g,15.9 mmol), pinacol diborane (4.43 g, 17.4 mmol), KOAc (4.68 g, 47.7mmol), Pd(dppf)Cl₂ (402 mg, 0.49 mmol) and dioxane (60 mL). The reactionmixture was purged with argon and then stirred at 90° C. under argon for20 h. The reaction mixture was cooled to room temperature, diluted withEtOAc, and dried over MgSO₄. The EtOAc was evaporated and the residuewas purified by column chromatography on silica gel (hexanes/EtOAc) togive compound 23a as a white solid (2.5 g, 50% yield, (m/z+H)=315).

Method B:

To a suspension of compound 29 (10 g, 31.8 mmol) in dioxane (320 mL) wasadded Pd(dppf)Cl₂.CH₂Cl₂ (0.82 g, 1.0 mmol) and reaction mixture wasdegassed by repeating argon/vacuum cycles. The suspension was stirredfor 10 min at room temperature, bis(pinacolato)diboron (8.9 g, 35.0mmol) and potassium acetate (0.97 g, 95.4 mmol) were added, and thereaction mixture was heated at 90° C. for 18 h under argon. Upon coolingto room temperature, the mixture was filtered through a pad of celiteand concentrated under reduced pressure. The residue was purified byautomated column chromatography on silica gel using a CombiFlash® system(5% ethyl acetate in hexanes) to give compound 23a as a pale brown solid(9.0 g, 90% yield, R=0.4, eluent (10% ethyl acetate in hexanes), LC/MS:m/z=315 [M+H]⁺, ¹H NMR (400 MHz, CD₃Cl): 7.67 (d, J=8.6 Hz, 2H),7.06-6.96 (m, 4H), 6.93 (d, J=8.6 Hz, 2H), 1.33 (s, 12H)).

Example 7

-   (2S,3R)-3-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (30a)-   (2S,3R)-2,3-dihydroxy-3-(6-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)propanamide    (30b)-   (2S,3R)-2,3-dihydroxy-3-(6-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2-yl)propanamide    (30c)-   (2S,3R)-3-(6-(4-((5-chloropyridin-2-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (30d)-   (2S,3R)-3-(6-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (30e)-   (2S,3R)-3-(6-(4-((6-chloropyridin-3-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (30f)-   (2S,3R)-3-(6-(4-(4-cyanophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (30g)

Compounds 23b-g were prepared according to the procedure described inExample 6 for preparing compound 23a.

The title compounds 30a-g were prepared following the same proceduredescribed in Example 3 for preparing compound 15 using compound 23a-gand AD-Mix-α:

(2S,3R)-3-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(30a) (off-white powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.19 (d, 2H),7.8-7.9 (m, 1H), 7.75 (d, 1H), 7.68 (d, 1H), 7.2-7.34 (m, 4H), 7.1-7.2(m, 2H), 7.08 (d, 2H), 5.0-5.5 (m, 3H), 4.2-4.5 (m, 1H); LC/MS:m/z=369.1 [M+H^(+]) (Calc: 368.36).

(2S,3R)-2,3-dihydroxy-3-(6-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)propanamide(30b) (off-white powder): ¹H-NMR (400 MHz, DMSO-d): δ 8.2 (d, 2H),7.7-7.85 (m, 4H), 7.5 (d, 1H), 7.2-7.34 (m, 6H), 5.0-5.5 (m, 3H),4.2-4.5 (m, 1H); LC/MS: m/z=419.1 [M+H+](Calc: 418.37).

(2S,3R)-2,3-dihydroxy-3-(6-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2-yl)propanamide(30c) (off-white powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.5 (s, 1H), 8.15(d, 1H), 8.05 (d, 2H), 7.6-7.8 (m, 2H), 7.4 (d, 1H), 7.0-7.3 (m, 5H),5.0-5.5 (m, 3H), 4.2-4.5 (m, 1H); LC/MS: m/z=420.1 [M+H](Calc: 419.35).

(2S,3R)-3-(6-(4-((5-chloropyridin-2-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(30d) (off-white powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.45 (s, 1H), 8.3(d, 2H), 8.0 (d, 1H), 7.8-7.9 (m, 2H), 7.5 (d, 1H), 7.1-7.3 (m, 5H),5.0-5.5 (m, 3H), 4.2-4.3 (m, 1H); LC/MS: m/z=386.1 [M+H⁺](Calc: 385.8).

(2S,3R)-3-(6-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(30e) (light-tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.25 (d, 2H),8.18 (d, 1H), 7.8-7.9 (m, 2H), 7.65 (s, 1H), 7.55 (d, 1H), 7.2-7.4 (m,5H), 5.0-5.5 (m, 3H), 4.2-4.3 (m, 1H); LC/MS: m/z=444.1 [M+H⁺] (Calc:443.38).

(2S,3R)-3-(6-(4-((6-chloropyridin-3-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(30f) (light-tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.3 (d, 1H), 8.18(d, 2H), 7.8-7.9 (m, 2H), 7.5-7.6 (m, 3H), 7.2-7.3 (m, 4H), 5.0-5.5 (m,3H), 4.2-4.3 (m, 1H); LC/MS: m/z=386.1 [M+H⁺] (Calc: 385.8).

(2S,3R)-3-(6-(4-(4-cyanophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(30g) (tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.2 (d, 1H), 8.18 (d,2H), 7.8-7.95 (m, 4H), 7.5 (d, 1H), 7.1-7.3 (m, 5H), 5.0-5.5 (m, 3H),4.2-4.3 (m, 1H); LC/MS: m/z=376.0 [M+H+](Calc: 375.38).

Example 8

-   (2R,3S)-3-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (31a)-   (2R,3S)-2,3-dihydroxy-3-(6-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)propanamide    (31b)-   (2R,3S)-2,3-dihydroxy-3-(6-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2-yl)propanamide    (31c)-   (2R,3S)-3-(6-(4-((5-chloropyridin-2-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (31d)-   (2R,3S)-3-(6-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (31e)-   (2R,3S)-3-(6-(4-((6-chloropyridin-3-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (31f)-   (2R,3S)-3-(6-(4-(4-cyanophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide    (31g)

The title compounds 31a-g were prepared following the same proceduredescribed in Example 3 for preparing compound 15 using compound 23a-gand AD-Mix-β:

(2R,3S)-3-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(31a) (light tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 7.9 (d, 2H),7.8-7.9 (m, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.35 (d, 1H), 6.9-7.2 (m,8H), 5.0-5.5 (m, 3H), 4.2-4.5 (m, 1H); LC/MS: m/z=369.1 [M+H⁺] (Calc:368.36).

(2R,3S)-2,3-dihydroxy-3-(6-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)propanamide(31b) (tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.2 (d, 2H), 7.7-7.9(m, 4H), 7.55 (d, 1H), 7.2-7.35 (m, 6H), 5.0-5.5 (m, 3H), 4.2-4.5 (m,1H); LC/MS: m/z=419.1 [M+H⁺] (Calc: 418.37).

(2R,3S)-2,3-dihydroxy-3-(6-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2-yl)propanamide(31c) (off-white powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.5 (s, 1H), 8.3(d, 1H), 8.2 (d, 2H), 7.8-7.9 (m, 2H), 7.45 (d, 1H), 7.2-7.4 (m, 5H),5.0-5.5 (m, 3H), 4.2-4.5 (m, 1H); LC/MS: m/z=420.1 [M+H+](Calc: 419.35).

(2R,3S)-3-(6-(4-((5-chloropyridin-2-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(31d) (light tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.25 (s, 1H),8.15 (d, 2H), 8.0 (d, 1H), 7.8-7.9 (m, 2H), 7.5 (d, 1H), 7.1-7.3 (m,5H), 5.0-5.5 (m, 3H), 4.2-4.3 (m, 1H); LC/MS: m/z=386.1 [M+H⁺](Calc:385.8).

(2R,3S)-3-(6-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(31e) (light-tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.25 (d, 2H),8.18 (d, 1H), 7.8-7.9 (m, 2H), 7.6 (s, 1H), 7.5 (d, 1H), 7.2-7.45 (m,5H), 5.0-5.5 (m, 3H), 4.2-4.3 (m, 1H); LC/MS: m/z=444.1 [M+H⁺] (Calc:443.38).

(2R,3S)-3-(6-(4-((6-chloropyridin-3-yl)oxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(31f) (light-tan powder): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.3 (s, 1H), 8.18(d, 2H), 7.8-7.9 (m, 2H), 7.5-7.6 (m, 3H), 7.15-7.3 (m, 4H), 5.0-5.5 (m,3H), 4.2-4.3 (m, 1H); LC/MS: m/z=386.1 [M+H⁺](Calc: 385.8).

(2R,3S)-3-(6-(4-(4-cyanophenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide(31g) (tan solid): ¹H-NMR (400 MHz, DMSO-d₆): δ 8.2 (d, 1H), 8.18 (d,2H), 7.8-7.9 (m, 4H), 7.5 (d, 1H), 7.1-7.3 (m, 6H), 5.0-5.5 (m, 3H),4.2-4.3 (m, 1H); LC/MS: m/z=376.0 [M+H⁺](Calc: 375.38).

Example 9

Compounds of the invention have been tested in the FLIPR^(TETRA)® orFLIPR® sodium dye assay with KCl assay and electrophysiology (EP) assayfor sodium channel blocking activity, which are described in detailabove. Representative values are presented in TABLE 2.

TABLE 2 Evaluation of the tested compounds as sodium channel (Na_(v))blockers FLIPR EP EP Na_(v) 1.7 Na_(v) 1.7 Na_(v) 1.7 COMPOUND IC₅₀ (μM)± SEM K_(i) (μM) ± SEM K_(r) (μM) ± SEM(2R,3S)-2,3-dihydroxy-3-(1-(4-((5- 0.314 ± 0.038(trifluoromethyl)pyridin-2- yl)oxy)phenyl)-1H-indol-3- yl)propanamide(5) (2S,3R)-ethyl 2,3-dihydroxy-3-(1-(4-((5- 0.152 ± 0.031(trifluoromethyl)pyridin-2- yl)oxy)phenyl)-1H-indol-3-yl)propanoate (6)(2S,3R)-2,3-dihydroxy-N-methyl-3-(1- 0.282 ± 0.002(4-((5-(trifluoromethyl)pyridin-2- yl)oxy)phenyl)-1H-indol-3-yl)propanamide (7) (2S,3R)-2,3-dihydroxy-3-(1-(4-((5- 0.193 ± 0.049(trifluoromethyl)pyridin-2- yl)oxy)phenyl)-1H-indol-3- yl)propanamide(8) (2S,3R)-ethyl 3-(6-(4-(3-cyano-4- 0.246 ± 0.031(trifluoromethyl)phenoxy)phenyl)pyridin- 2-yl)-2,3-dihydroxypropanoate(14) (2S,3R)-3-(6-(4-(3-cyano-4- 0.304 ± 0.022 0.917 ± 0.050 32.935 ±6.890 (trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2,3-dihydroxypropanamide (15) (2R,3S)-3-(6-(4-(3-cyano-4- 0.244 ±0.050 0.347 ± 0.070 17.088 ± 4.240(trifluoromethyl)phenoxy)phenyl)pyridin- 2-yl)-2,3-dihydroxypropanamide(19) (2R,3S)-3-(2-(4-(4-fluorophenoxy)- 0.625 ± 0.058 2.262 ± 0.61097.909 ± 23.070 phenyl)pyrimidin-4-yl)-2,3-dihydroxy- propanamide (26)

  (30b) 0.130 ± 0.025

  (31b) 0.383 ± 0.072

  (30a) 1.409 ± 0.281

  (31a) 1.845 ± 0.309

  (30c) 0.711 ± 0.050

  (31c) 1.691 ± 0.019

  (30d) 1.190 ± 0.074

  (31d) 1.439 ± 0.078

  (30e) 0.461 ± 0.045

  (31e) 0.489 ± 0.040

  (30f) 0.376 ± 0.057

  (31f) 0.804 ± 0.044

  (30g) 0.262 ± 0.017

  (31g) 0.690 ± 0.071

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound having the Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: Hetis pyrimidinyl or a 9-ring-membered heteroaryl having carbon atoms andat least one nitrogen atom; G is G¹ or G², wherein G¹ is

and G² is

R¹ and R² are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl,alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy,haloalkylcarbonyl, and optionally substituted arylcarbonyl; R³ isselected from the group consisting of hydrogen, alkyl, hydroxyalkyl,alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,and dialkylaminoalkyl; each R is independently alkyl, alkenyl, alkynyl,halogen, hydroxy, cyano, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino,alkylcarbonyloxy, carboxy, aminosulfonyl, alkylsulfonylamino,alkoxycarbonyl, aminocarbonylalkyl, (alkylaminocarbonyl)alkyl,(dialkylaminocarbonyl)alkyl, —CH(OH)C(═O)NH₂, —CH(OH)CH₂NR^(a)R^(b),—CH(NR^(a)R^(b))CH₂OH, or —CH₂CH(NR^(a)R^(b))CH₂OH, where R^(a) andR^(b) are each independently hydrogen or C₁₋₆ alkyl; n is 0, 1, 2, 3, 4,5, or 6; A is

wherein A¹ is aryl or heteroaryl, any of which is optionallysubstituted; R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl,hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl,alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl,alkoxy, carboxy, and aminocarbonyl; and X is —O—, —S—, —SO—, —SO₂—,—CH₂—, —NR⁴—, —N(R⁵)SO₂—, or —SO₂N(R⁶)—, wherein R⁴, R⁵, and R⁶ are eachindependently hydrogen or alkyl. 2-15. (canceled)
 16. The compound ofclaim 1, wherein said Het is indolyl and n is n2, having the Formula IV:

or a pharmaceutically acceptable salt, or solvate thereof, wherein A, G,and R are as defined in claim 1, and n2 is 0, 1, 2, 3, 4, or
 5. 17. Thecompound of claim 16, having the Formula V:

or a pharmaceutically acceptable salt, or solvate thereof, wherein A, G,R, and n2 are as defined in claim 16, and n2 is 0 or
 1. 18-20.(canceled)
 21. The compound of claim 1, wherein said Het is1H-pyrrolo[3,2-b]pyridinyl and n is n4, having the Formula VIII:

or a pharmaceutically acceptable salt, or solvate thereof, wherein A, G,and R are as defined in claim 1, and n4 is 0, 1, 2, 3, or
 4. 22. Thecompound of claim 1, wherein said Het is 1H-pyrrolo[2,3-c]pyridinyl andn is n5, having the Formula IX:

or a pharmaceutically acceptable salt or solvate thereof, wherein A, G,and R are as defined in claim 1, and n5 is 0, 1, 2, 3, or
 4. 23.(canceled)
 24. The compound of claim 1, having the Formula XI:

or a pharmaceutically acceptable salt, or solvate thereof.
 25. Thecompound of claim 1, wherein G is G¹, and R¹ and R² are both hydrogen.26. (canceled)
 27. The compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, wherein G is G¹, R¹ is hydrogen, andR² is selected from the group consisting of alkyl, alkylsulfonyl,alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionallysubstituted arylcarbonyl.
 28. (canceled)
 29. The compound of claim 1, ora pharmaceutically acceptable salt or solvate thereof, wherein G is G¹,R¹ is hydrogen, and R² is hydrogen, hydroxy, alkyl, or hydroxyalkyl. 30.The compound of claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein G is G¹ and is selected from the groupconsisting of


31. The compound of claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein G is G², and R³ is hydrogen or alkyl. 32.(canceled)
 33. The compound of claim 31, or a pharmaceuticallyacceptable salt or solvate thereof, wherein G is G² and is selected fromthe group consisting of

34-35. (canceled)
 36. The compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, wherein A is A^(a) having thestructure:

wherein X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR⁴—, —N(R⁵)SO₂—, or—SO₂N(R⁶)—; R⁴, R⁵, and R⁶ are as defined in claim 1, and R⁷, R⁸, R⁹,and R¹⁰ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl,hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido,acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl. 37-38. (canceled)
 39. The compound of claim 1, having theFormula X:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ andR² are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl, and R⁷, R⁸, R⁹, and R¹⁰ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro,amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino,thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl. 40-44. (canceled)
 45. The compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, wherein A is A^(c)having the structure:

wherein X is —O—, —S—, —SO—, —SO₂—, —CH₂—, —NR⁴—, —N(R⁵)SO₂—, or—SO₂N(R⁶)—; and R⁷, R⁸, R¹¹, and R¹² are each independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.
 46. (canceled) 47.The compound of claim 1, or a pharmaceutically acceptable salt orsolvate thereof, wherein A is A^(d) having the structure:

wherein R⁷, R⁸, R¹¹, and R¹² are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl.
 48. The compound ofclaim 1, having the Formula XIV:

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ andR² are each independently selected from the group consisting ofhydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, andoptionally substituted arylcarbonyl, and R⁷, R⁸, R¹¹, and R¹² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro,amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino,thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, andaminocarbonyl. 49-53. (canceled)
 54. The compound of claim 1, and 53, ora pharmaceutically acceptable salt or solvate thereof, wherein A isA^(f) having the structure:

wherein R⁷, R⁸, R¹¹, and R¹² are each independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen,haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide,carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido,mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl. 55-57. (canceled) 58.The compound of claim 1, wherein said compound is2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,ethyl2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanoate,2,3-dihydroxy-N-methyl-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,3-(2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)-2,3-dihydroxypropanamide;(2R,3S)-2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,(2S,3R)-ethyl2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanoate,(2S,3R)-2,3-dihydroxy-N-methyl-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,(2S,3R)-2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propanamide,or(2R,3S)-3-(2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)-2,3-dihydroxypropanamide;or a pharmaceutically acceptable salt or solvate thereof. 59-61.(canceled)
 62. A pharmaceutical composition, comprising the compound ofclaim 1, or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier. 63-66. (canceled)
 67. A method fortreating pain in a mammal, comprising administering an effective amountof a compound as claimed in claim 1 or a pharmaceutically acceptablesalt, or solvate thereof, to a mammal in need of such treatment. 68-69.(canceled)
 70. The method of claim 67, wherein said pain is selectedfrom the group consisting of chronic pain, inflammatory pain,neuropathic pain, postsurgical pain, acute pain, and surgical pain. 71.A method of modulating sodium channels in a mammal, comprisingadministering to the mammal at least one compound as claimed in claim 1or a pharmaceutically acceptable salt or solvate thereof. 72-81.(canceled)